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Bibliography on: Energetics and Mitochondrial Evolution

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ESP: PubMed Auto Bibliography 22 May 2024 at 01:56 Created: 

Energetics and Mitochondrial Evolution

Mitochondria are the energy-producing "engines" that provide the power to drive eukaryotic cells. The energy output of hundreds, or thousands, of mitochondria allowed eukaryotic cells to increase in size 1000-fold, or more, over the size of prokaryotics cells. This increase in size allowed an escape from the constraints of low Reynolds numbers and, for the first time, life could function in a way where mechanism, and thus morphology, mattered. Evolution began to shape morphology, allowing the emergence of the multicellular eukaryotic biosphere — the visible living world.

Created with PubMed® Query: ( mitochondria AND evolution AND (energetics OR "energy metabolism") ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2024-05-18
CmpDate: 2024-05-18

Fernández-Moncada I, Rodrigues RS, Fundazuri UB, et al (2024)

Type-1 cannabinoid receptors and their ever-expanding roles in brain energy processes.

Journal of neurochemistry, 168(5):693-703.

The brain requires large quantities of energy to sustain its functions. At the same time, the brain is isolated from the rest of the body, forcing this organ to develop strategies to control and fulfill its own energy needs. Likely based on these constraints, several brain-specific mechanisms emerged during evolution. For example, metabolically specialized cells are present in the brain, where intercellular metabolic cycles are organized to separate workload and optimize the use of energy. To orchestrate these strategies across time and space, several signaling pathways control the metabolism of brain cells. One of such controlling systems is the endocannabinoid system, whose main signaling hub in the brain is the type-1 cannabinoid (CB1) receptor. CB1 receptors govern a plethora of different processes in the brain, including cognitive function, emotional responses, or feeding behaviors. Classically, the mechanisms of action of CB1 receptors on brain function had been explained by its direct targeting of neuronal synaptic function. However, new discoveries have challenged this view. In this review, we will present and discuss recent data about how a small fraction of CB1 receptors associated to mitochondrial membranes (mtCB1), are able to exert a powerful control on brain functions and behavior. mtCB1 receptors impair mitochondrial functions both in neurons and astrocytes. In the latter cells, this effect is linked to an impairment of astrocyte glycolytic function, resulting in specific behavioral outputs. Finally, we will discuss the potential implications of (mt)CB1 expression on oligodendrocytes and microglia metabolic functions, with the aim to encourage interdisciplinary approaches to better understand the role of (mt)CB1 receptors in brain function and behavior.

RevDate: 2024-04-11

Coale TH, Loconte V, Turk-Kubo KA, et al (2024)

Nitrogen-fixing organelle in a marine alga.

Science (New York, N.Y.), 384(6692):217-222.

Symbiotic interactions were key to the evolution of chloroplast and mitochondria organelles, which mediate carbon and energy metabolism in eukaryotes. Biological nitrogen fixation, the reduction of abundant atmospheric nitrogen gas (N2) to biologically available ammonia, is a key metabolic process performed exclusively by prokaryotes. Candidatus Atelocyanobacterium thalassa, or UCYN-A, is a metabolically streamlined N2-fixing cyanobacterium previously reported to be an endosymbiont of a marine unicellular alga. Here we show that UCYN-A has been tightly integrated into algal cell architecture and organellar division and that it imports proteins encoded by the algal genome. These are characteristics of organelles and show that UCYN-A has evolved beyond endosymbiosis and functions as an early evolutionary stage N2-fixing organelle, or "nitroplast."

RevDate: 2024-04-08
CmpDate: 2024-04-08

Nevarez-Lopez CA, Muhlia-Almazan A, Gamero-Mora E, et al (2024)

The branched mitochondrial respiratory chain from the jellyfish Stomolophus sp2 as a probable adaptive response to environmental changes.

Journal of bioenergetics and biomembranes, 56(2):101-115.

During their long evolutionary history, jellyfish have faced changes in multiple environmental factors, to which they may selectively fix adaptations, allowing some species to survive and inhabit diverse environments. Previous findings have confirmed the jellyfish's ability to synthesize large ATP amounts, mainly produced by mitochondria, in response to environmental challenges. This study characterized the respiratory chain from the mitochondria of the jellyfish Stomolophus sp2 (previously misidentified as Stomolophus meleagris). The in-gel activity from isolated jellyfish mitochondria confirmed that the mitochondrial respiratory chain contains the four canonical complexes I to IV and F0F1-ATP synthase. Specific additional activity bands, immunodetection, and mass spectrometry identification confirmed the occurrence of four alternative enzymes integrated into a branched mitochondrial respiratory chain of Stomolophus sp2: an alternative oxidase and three dehydrogenases (two NADH type II enzymes and a mitochondrial glycerol-3-phosphate dehydrogenase). The analysis of each transcript sequence, their phylogenetic relationships, and each protein's predicted models confirmed the mitochondrial alternative enzymes' identity and specific characteristics. Although no statistical differences were found among the mean values of transcript abundance of each enzyme in the transcriptomes of jellyfish exposed to three different temperatures, it was confirmed that each gene was expressed at all tested conditions. These first-time reported enzymes in cnidarians suggest the adaptative ability of jellyfish's mitochondria to display rapid metabolic responses, as previously described, to maintain energetic homeostasis and face temperature variations due to climate change.

RevDate: 2024-03-16

Keeling PJ, Mtawali M, Trznadel M, et al (2024)

Parallel functional reduction in the mitochondria of apicomplexan parasites.

European journal of protistology, 94:126065 pii:S0932-4739(24)00015-4 [Epub ahead of print].

Extreme functional reduction of mitochondria has taken place in parallel in many distantly related lineages of eukaryotes, leading to a number of recurring metabolic states with variously lost electron transport chain (ETC) complexes, loss of the tricarboxylic acid (TCA) cycle, and/or loss of the mitochondrial genome. The resulting mitochondria-related organelles (MROs) are generally structurally reduced and in the most extreme cases barely recognizable features of the cell with no role in energy metabolism whatsoever (e.g., mitosomes, which generally only make iron-sulfur clusters). Recently, a wide diversity of MROs were discovered to be hiding in plain sight: in gregarine apicomplexans. This diverse group of invertebrate parasites has been known and observed for centuries, but until recent applications of culture-free genomics, their mitochondria were unremarkable. The genomics, however, showed that mitochondrial function has reduced in parallel in multiple gregarine lineages to several different endpoints, including the most reduced mitosomes. Here we review this remarkable case of parallel evolution of MROs, and some of the interesting questions this work raises.

RevDate: 2024-03-13

Vesala L, Basikhina Y, Tuomela T, et al (2024)

Mitochondrial perturbation in immune cells enhances cell-mediated innate immunity in Drosophila.

BMC biology, 22(1):60.

BACKGROUND: Mitochondria participate in various cellular processes including energy metabolism, apoptosis, autophagy, production of reactive oxygen species, stress responses, inflammation and immunity. However, the role of mitochondrial metabolism in immune cells and tissues shaping the innate immune responses are not yet fully understood. We investigated the effects of tissue-specific mitochondrial perturbation on the immune responses at the organismal level. Genes for oxidative phosphorylation (OXPHOS) complexes cI-cV were knocked down in the fruit fly Drosophila melanogaster, targeting the two main immune tissues, the fat body and the immune cells (hemocytes).

RESULTS: While OXPHOS perturbation in the fat body was detrimental, hemocyte-specific perturbation led to an enhanced immunocompetence. This was accompanied by the formation of melanized hemocyte aggregates (melanotic nodules), a sign of activation of cell-mediated innate immunity. Furthermore, the hemocyte-specific OXPHOS perturbation induced immune activation of hemocytes, resulting in an infection-like hemocyte profile and an enhanced immune response against parasitoid wasp infection. In addition, OXPHOS perturbation in hemocytes resulted in mitochondrial membrane depolarization and upregulation of genes associated with the mitochondrial unfolded protein response.

CONCLUSIONS: Overall, we show that while the effects of mitochondrial perturbation on immune responses are highly tissue-specific, mild mitochondrial dysfunction can be beneficial in immune-challenged individuals and contributes to variation in infection outcomes among individuals.

RevDate: 2024-02-02

Muñoz-Gómez SA (2024)

The energetic costs of cellular complexity in evolution.

Trends in microbiology pii:S0966-842X(24)00003-9 [Epub ahead of print].

The evolutionary history of cells has been marked by drastic increases in complexity. Some hypothesize that such cellular complexification requires a massive energy flux as the origin of new features is hypothetically more energetically costly than their evolutionary maintenance. However, it remains unclear how increases in cellular complexity demand more energy. I propose that the early evolution of new genes with weak functions imposes higher energetic costs by overexpression before their functions are evolutionarily refined. In the long term, the accumulation of new genes deviates resources away from growth and reproduction. Accrued cellular complexity further requires additional infrastructure for its maintenance. Altogether, this suggests that larger and more complex cells are defined by increased survival but lower reproductive capacity.

RevDate: 2024-01-24
CmpDate: 2024-01-24

Li X, Li W, Huo J, et al (2024)

[Identification and expression analysis of citrate synthase 3 gene family members in apple].

Sheng wu gong cheng xue bao = Chinese journal of biotechnology, 40(1):137-149.

As one of the key enzymes in cell metabolism, the activity of citrate synthase 3 (CS3) regulates the substance and energy metabolism of organisms. The protein members of CS3 family were identified from the whole genome of apple, and bioinformatics analysis was performed and expression patterns were analyzed to provide a theoretical basis for studying the potential function of CS3 gene in apple. BLASTp was used to identify members of the apple CS3 family based on the GDR database, and the basic information of CS3 protein sequence, subcellular localization, domain composition, phylogenetic relationship and chromosome localization were analyzed by Pfam, SMART, MEGA5.0, clustalx.exe, ExPASy Proteomics Server, MEGAX, SOPMA, MEME, WoLF PSORT and other software. The tissue expression and inducible expression characteristics of 6 CS3 genes in apple were determined by acid content and real-time fluorescence quantitative polymerase chain reaction (qRT-PCR). Apple CS3 gene family contains 6 members, and these CS3 proteins contain 473-608 amino acid residues, with isoelectric point distribution between 7.21 and 8.82. Subcellular localization results showed that CS3 protein was located in mitochondria and chloroplasts, respectively. Phylogenetic analysis divided them into 3 categories, and the number of genes in each subfamily was 2. Chromosome localization analysis showed that CS3 gene was distributed on different chromosomes of apple. The secondary structure of protein is mainly α-helix, followed by random curling, and the proportion of β-angle is the smallest. The 6 members were all expressed in different apple tissues. The overall expression trend from high to low was the highest relative expression content of MdCS3.4, followed by MdCS3.6, and the relative expression level of other members was in the order of MdCS3.3 > MdCS3.2 > MdCS3.1 > MdCS3.5. qRT-PCR results showed that MdCS3.1 and MdCS3.3 genes had the highest relative expression in the pulp of 'Chengji No. 1' with low acid content, and MdCS3.2 and MdCS3.3 genes in the pulp of 'Asda' with higher acid content had the highest relative expression. Therefore, in this study, the relative expression of CS3 gene in apple cultivars with different acid content in different apple varieties was detected, and its role in apple fruit acid synthesis was analyzed. The experimental results showed that the relative expression of CS3 gene in different apple varieties was different, which provided a reference for the subsequent study of the quality formation mechanism of apple.

RevDate: 2024-01-09
CmpDate: 2024-01-09

Prokkola JM, Chew KK, Anttila K, et al (2024)

Tissue-specific metabolic enzyme levels covary with whole-animal metabolic rates and life-history loci via epistatic effects.

Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 379(1896):20220482.

Metabolic rates, including standard (SMR) and maximum (MMR) metabolic rate have often been linked with life-history strategies. Variation in context- and tissue-level metabolism underlying SMR and MMR may thus provide a physiological basis for life-history variation. This raises a hypothesis that tissue-specific metabolism covaries with whole-animal metabolic rates and is genetically linked to life history. In Atlantic salmon (Salmo salar), variation in two loci, vgll3 and six6, affects life history via age-at-maturity as well as MMR. Here, using individuals with known SMR and MMR with different vgll3 and six6 genotype combinations, we measured proxies of mitochondrial density and anaerobic metabolism, i.e. maximal activities of the mitochondrial citrate synthase (CS) and lactate dehydrogenase (LDH) enzymes, in four tissues (heart, intestine, liver, white muscle) across low- and high-food regimes. We found enzymatic activities were related to metabolic rates, mainly SMR, in the intestine and heart. Individual loci were not associated with the enzymatic activities, but we found epistatic effects and genotype-by-environment interactions in CS activity in the heart and epistasis in LDH activity in the intestine. These effects suggest that mitochondrial density and anaerobic capacity in the heart and intestine may partly mediate variation in metabolic rates and life history via age-at-maturity. This article is part of the theme issue 'The evolutionary significance of variation in metabolic rates'.

RevDate: 2023-12-27

Shen Q, Yuan Y, J Jin (2023)

[Relationship between Notch signaling pathway and mitochondrial energy metabolism].

Zhonghua wei zhong bing ji jiu yi xue, 35(12):1321-1326.

Notch signaling pathway is a highly conserved signaling pathway in the process of evolution. It is composed of three parts: Notch receptor, ligand and effector molecules responsible for intracellular signal transduction. It plays an important role in cell proliferation, differentiation, development, migration, apoptosis and other processes, and has a regulatory effect on tissue homeostasis and homeostasis. Mitochondria are the sites of oxidative metabolism in eukaryotes, where sugars, fats and proteins are finally oxidized to release energy. In recent years, the regulation of Notch signaling pathway on mitochondrial energy metabolism has attracted more and more attention. A large number of data have shown that Notch signaling pathway has a significant effect on mitochondrial energy metabolism, but the relationship between Notch signaling pathway and mitochondrial energy metabolism needs to be specifically and systematically discussed. In this paper, the relationship between Notch signaling pathway and mitochondrial energy metabolism is reviewed, in order to improve the understanding of them and provide new ideas for the treatment of related diseases.

RevDate: 2023-12-19

He Z, Fang Y, Zhang F, et al (2023)

Adenine nucleotide translocase 2 (Ant2) is required for individualization of spermatogenesis of Drosophila melanogaster.

Insect science [Epub ahead of print].

Successful completion of spermatogenesis is crucial for the perpetuation of the species. In Drosophila, spermatid individualization, a process involving changes in mitochondrial structure and function is critical to produce functional mature sperm. Ant2, encoding a mitochondrial adenine nucleotide translocase, is highly expressed in male testes and plays a role in energy metabolism in the mitochondria. However, its molecular function remains unclear. Here, we identified an important role of Ant2 in spermatid individualization. In Ant2 knockdown testes, spermatid individualization complexes composed of F-actin cones exhibited a diffuse distribution, and mature sperms were absent in the seminal vesicle, thus leading to male sterility. The most striking effects in Ant2-knockdown spermatids were decrease in tubulin polyglycylation and disruption of proper mitochondria derivatives function. Excessive apoptotic cells were also observed in Ant2-knockdown testes. To further investigate the phenotype of Ant2 knockdown in testes at the molecular level, complementary transcriptome and proteome analyses were performed. At the mRNA level, 868 differentially expressed genes were identified, of which 229 genes were upregulated and 639 were downregulated induced via Ant2 knockdown. iTRAQ-labeling proteome analysis revealed 350 differentially expressed proteins, of which 117 proteins were upregulated and 233 were downregulated. The expression of glutathione transferase (GstD5, GstE5, GstE8, and GstD3), proteins involved in reproduction were significantly regulated at both the mRNA and protein levels. These results indicate that Ant2 is crucial for spermatid maturation by affecting mitochondrial morphogenesis.

RevDate: 2023-12-16
CmpDate: 2023-12-16

Zuccoli GS, Nascimento JM, Moraes-Vieira PM, et al (2023)

Mitochondrial, cell cycle control and neuritogenesis alterations in an iPSC-based neurodevelopmental model for schizophrenia.

European archives of psychiatry and clinical neuroscience, 273(8):1649-1664.

Schizophrenia is a severe psychiatric disorder of neurodevelopmental origin that affects around 1% of the world's population. Proteomic studies and other approaches have provided evidence of compromised cellular processes in the disorder, including mitochondrial function. Most of the studies so far have been conducted on postmortem brain tissue from patients, and therefore, do not allow the evaluation of the neurodevelopmental aspect of the disorder. To circumvent that, we studied the mitochondrial and nuclear proteomes of neural stem cells (NSCs) and neurons derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients versus healthy controls to assess possible alterations related to energy metabolism and mitochondrial function during neurodevelopment in the disorder. Our results revealed differentially expressed proteins in pathways related to mitochondrial function, cell cycle control, DNA repair and neuritogenesis and their possible implication in key process of neurodevelopment, such as neuronal differentiation and axonal guidance signaling. Moreover, functional analysis of NSCs revealed alterations in mitochondrial oxygen consumption in schizophrenia-derived cells and a tendency of higher levels of intracellular reactive oxygen species (ROS). Hence, this study shows evidence that alterations in important cellular processes are present during neurodevelopment and could be involved with the establishment of schizophrenia, as well as the phenotypic traits observed in adult patients. Neural stem cells (NSCs) and neurons were derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients and controls. Proteomic analyses were performed on the enriched mitochondrial and nuclear fractions of NSCs and neurons. Whole-cell proteomic analysis was also performed in neurons. Our results revealed alteration in proteins related to mitochondrial function, cell cycle control, among others. We also performed energy pathway analysis and reactive oxygen species (ROS) analysis of NSCs, which revealed alterations in mitochondrial oxygen consumption and a tendency of higher levels of intracellular ROS in schizophrenia-derived cells.

RevDate: 2023-12-05

Fernández Miyakawa ME, Casanova NA, MH Kogut (2023)

How did antibiotic growth promoters increase growth and feed efficiency in poultry?.

Poultry science, 103(2):103278 pii:S0032-5791(23)00797-6 [Epub ahead of print].

It has been hypothesized that reducing the bioenergetic costs of gut inflammation as an explanation for the effect of antibiotic growth promoters (AGPs) on animal efficiency, framing some observations but not explaining the increase in growth rate or the prevention of infectious diseases. The host's ability to adapt to alterations in environmental conditions and to maintain health involves managing all physiological interactions that regulate homeostasis. Thus, metabolic pathways are vital in regulating physiological health as the energetic demands of the host guides most biological functions. Mitochondria are not only the metabolic heart of the cell because of their role in energy metabolism and oxidative phosphorylation, but also a central hub of signal transduction pathways that receive messages about the health and nutritional states of cells and tissues. In response, mitochondria direct cellular and tissue physiological alterations throughout the host. The endosymbiotic theory suggests that mitochondria evolved from prokaryotes, emphasizing the idea that these organelles can be affected by some antibiotics. Indeed, therapeutic levels of several antibiotics can be toxic to mitochondria, but subtherapeutic levels may improve mitochondrial function and defense mechanisms by inducing an adaptive response of the cell, resulting in mitokine production which coordinates an array of adaptive responses of the host to the stressor(s). This adaptive stress response is also observed in several bacteria species, suggesting that this protective mechanism has been preserved during evolution. Concordantly, gut microbiome modulation by subinhibitory concentration of AGPs could be the result of direct stimulation rather than inhibition of determined microbial species. In eukaryotes, these adaptive responses of the mitochondria to internal and external environmental conditions, can promote growth rate of the organism as an evolutionary strategy to overcome potential negative conditions. We hypothesize that direct and indirect subtherapeutic AGP regulation of mitochondria functional output can regulate homeostatic control mechanisms in a manner similar to those involved with disease tolerance.

RevDate: 2023-12-04

Charrasse S, Poquillon T, Saint-Omer C, et al (2023)

Quantitative assessment of mitochondrial morphology relevant for studies on cellular health and environmental toxicity.

Computational and structural biotechnology journal, 21:5609-5619.

Mitochondria are essential organelles that play crucial roles in cellular energy metabolism, calcium signaling and apoptosis. Their importance in tissue homeostasis and stress responses, combined to their ability to transition between various structural and functional states, make them excellent organelles for monitoring cellular health. Quantitative assessment of mitochondrial morphology can therefore provide valuable insights into environmentally-induced cell damage. High-content screening (HCS) provides a powerful tool for analyzing organelles and cellular substructures. We developed a fully automated and miniaturized HCS wet-plus-dry pipeline (MITOMATICS) exploiting mitochondrial morphology as a marker for monitoring cellular health or damage. MITOMATICS uses an in-house, proprietary software (MitoRadar) to enable fast, exhaustive and cost-effective analysis of mitochondrial morphology and its inherent diversity in live cells. We applied our pipeline and big data analytics software to assess the mitotoxicity of selected chemicals, using the mitochondrial uncoupler CCCP as an internal control. Six different pesticides (inhibiting complexes I, II and III of the mitochondrial respiratory chain) were tested as individual compounds and five other pesticides present locally in Occitanie (Southern France) were assessed in combination to determine acute mitotoxicity. Our results show that the assayed pesticides exhibit specific signatures when used as single compounds or chemical mixtures and that they function synergistically to impact mitochondrial architecture. Study of environment-induced mitochondrial damage has the potential to open new fields in mechanistic toxicology, currently underexplored by regulatory toxicology and exposome research. Such exploration could inform health policy guidelines and foster pharmacological intervention, water, air and soil pollution control and food safety.

RevDate: 2023-12-04
CmpDate: 2023-12-04

Fähnrich A, Stephan I, Hirose M, et al (2023)

North and East African mitochondrial genetic variation needs further characterization towards precision medicine.

Journal of advanced research, 54:59-76.

INTRODUCTION: Mitochondria are maternally inherited cell organelles with their own genome, and perform various functions in eukaryotic cells such as energy production and cellular homeostasis. Due to their inheritance and manifold biological roles in health and disease, mitochondrial genetics serves a dual purpose of tracing the history as well as disease susceptibility of human populations across the globe. This work requires a comprehensive catalogue of commonly observed genetic variations in the mitochondrial DNAs for all regions throughout the world. So far, however, certain regions, such as North and East Africa have been understudied.

OBJECTIVES: To address this shortcoming, we have created the most comprehensive quality-controlled North and East African mitochondrial data set to date and use it for characterizing mitochondrial genetic variation in this region.

METHODS: We compiled 11 published cohorts with novel data for mitochondrial genomes from 159 Sudanese individuals. We combined these 641 mitochondrial sequences with sequences from the 1000 Genomes (n = 2504) and the Human Genome Diversity Project (n = 828) and used the tool haplocheck for extensive quality control and detection of in-sample contamination, as well as Nanopore long read sequencing for haplogroup validation of 18 samples.

RESULTS: Using a subset of high-coverage mitochondrial sequences, we predict 15 potentially novel haplogroups in North and East African subjects and observe likely phylogenetic deviations from the established PhyloTree reference for haplogroups L0a1 and L2a1.

CONCLUSION: Our findings demonstrate common hitherto unexplored variants in mitochondrial genomes of North and East Africa that lead to novel phylogenetic relationships between haplogroups present in these regions. These observations call for further in-depth population genetic studies in that region to enable the prospective use of mitochondrial genetic variation for precision medicine.

RevDate: 2023-11-25

Nusir A, Sinclair P, N Kabbani (2023)

Mitochondrial Proteomes in Neural Cells: A Systematic Review.

Biomolecules, 13(11): pii:biom13111638.

Mitochondria are ancient endosymbiotic double membrane organelles that support a wide range of eukaryotic cell functions through energy, metabolism, and cellular control. There are over 1000 known proteins that either reside within the mitochondria or are transiently associated with it. These mitochondrial proteins represent a functional subcellular protein network (mtProteome) that is encoded by mitochondrial and nuclear genomes and significantly varies between cell types and conditions. In neurons, the high metabolic demand and differential energy requirements at the synapses are met by specific modifications to the mtProteome, resulting in alterations in the expression and functional properties of the proteins involved in energy production and quality control, including fission and fusion. The composition of mtProteomes also impacts the localization of mitochondria in axons and dendrites with a growing number of neurodegenerative diseases associated with changes in mitochondrial proteins. This review summarizes the findings on the composition and properties of mtProteomes important for mitochondrial energy production, calcium and lipid signaling, and quality control in neural cells. We highlight strategies in mass spectrometry (MS) proteomic analysis of mtProteomes from cultured cells and tissue. The research into mtProteome composition and function provides opportunities in biomarker discovery and drug development for the treatment of metabolic and neurodegenerative disease.

RevDate: 2023-11-14
CmpDate: 2023-11-14

Politis-Barber V, Petrick HL, Raajendiran A, et al (2022)

Ckmt1 is Dispensable for Mitochondrial Bioenergetics Within White/Beige Adipose Tissue.

Function (Oxford, England), 3(5):zqac037.

Within brown adipose tissue (BAT), the brain isoform of creatine kinase (CKB) has been proposed to regulate the regeneration of ADP and phosphocreatine in a futile creatine cycle (FCC) that stimulates energy expenditure. However, the presence of FCC, and the specific creatine kinase isoforms regulating this theoretical model within white adipose tissue (WAT), remains to be fully elucidated. In the present study, creatine did not stimulate respiration in cultured adipocytes, isolated mitochondria or mouse permeabilized WAT. Additionally, while creatine kinase ubiquitous-type, mitochondrial (CKMT1) mRNA and protein were detected in human WAT, shRNA-mediated reductions in Ckmt1 did not decrease submaximal respiration in cultured adipocytes, and ablation of CKMT1 in mice did not alter energy expenditure, mitochondrial responses to pharmacological β3-adrenergic activation (CL 316, 243) or exacerbate the detrimental metabolic effects of consuming a high-fat diet. Taken together, these findings solidify CKMT1 as dispensable in the regulation of energy expenditure, and unlike in BAT, they do not support the presence of FCC within WAT.

RevDate: 2023-11-13

Da Costa RT, Riggs LM, ME Solesio (2023)

Inorganic polyphosphate and the regulation of mitochondrial physiology.

Biochemical Society transactions pii:233737 [Epub ahead of print].

Inorganic polyphosphate (polyP) is an ancient polymer that is well-conserved throughout evolution. It is formed by multiple subunits of orthophosphates linked together by phosphoanhydride bonds. The presence of these bonds, which are structurally similar to those found in ATP, and the high abundance of polyP in mammalian mitochondria, suggest that polyP could be involved in the regulation of the physiology of the organelle, especially in the energy metabolism. In fact, the scientific literature shows an unequivocal role for polyP not only in directly regulating oxidative a phosphorylation; but also in the regulation of reactive oxygen species metabolism, mitochondrial free calcium homeostasis, and the formation and opening of mitochondrial permeability transitions pore. All these processes are closely interconnected with the status of mitochondrial bioenergetics and therefore play a crucial role in maintaining mitochondrial and cell physiology. In this invited review, we discuss the main scientific literature regarding the regulatory role of polyP in mammalian mitochondrial physiology, placing a particular emphasis on its impact on energy metabolism. Although the effects of polyP on the physiology of the organelle are evident; numerous aspects, particularly within mammalian cells, remain unclear and require further investigation. These aspects encompass, for example, advancing the development of more precise analytical methods, unraveling the mechanism responsible for sensing polyP levels, and understanding the exact molecular mechanism that underlies the effects of polyP on mitochondrial physiology. By increasing our understanding of the biology of this ancient and understudied polymer, we could unravel new pharmacological targets in diseases where mitochondrial dysfunction, including energy metabolism dysregulation, has been broadly described.

RevDate: 2023-07-31

Preziuso A, Piccirillo S, Cerqueni G, et al (2023)

Exploring the Role of NCX1 and NCX3 in an In Vitro Model of Metabolism Impairment: Potential Neuroprotective Targets for Alzheimer's Disease.

Biology, 12(7):.

Alzheimer's disease (AD) is a widespread neurodegenerative disorder, affecting a large number of elderly individuals worldwide. Mitochondrial dysfunction, metabolic alterations, and oxidative stress are regarded as cooperating drivers of the progression of AD. In particular, metabolic impairment amplifies the production of reactive oxygen species (ROS), resulting in detrimental alterations to intracellular Ca[2+] regulatory processes. The Na[+]/Ca[2+] exchanger (NCX) proteins are key pathophysiological determinants of Ca[2+] and Na[+] homeostasis, operating at both the plasma membrane and mitochondria levels. Our study aimed to explore the role of NCX1 and NCX3 in retinoic acid (RA) differentiated SH-SY5Y cells treated with glyceraldehyde (GA), to induce impairment of the default glucose metabolism that typically precedes Aβ deposition or Tau protein phosphorylation in AD. By using an RNA interference-mediated approach to silence either NCX1 or NCX3 expression, we found that, in GA-treated cells, the knocking-down of NCX3 ameliorated cell viability, increased the intracellular ATP production, and reduced the oxidative damage. Remarkably, NCX3 silencing also prevented the enhancement of Aβ and pTau levels and normalized the GA-induced decrease in NCX reverse-mode activity. By contrast, the knocking-down of NCX1 was totally ineffective in preventing GA-induced cytotoxicity except for the increase in ATP synthesis. These findings indicate that NCX3 and NCX1 may differently influence the evolution of AD pathology fostered by glucose metabolic dysfunction, thus providing a potential target for preventing AD.

RevDate: 2023-07-10

Wan H, Zhang Y, Wu L, et al (2023)

Evolution of cytosolic and organellar invertases empowered the colonization and thriving of land plants.

Plant physiology pii:7222356 [Epub ahead of print].

The molecular innovation underpinning efficient carbon and energy metabolism during evolution of land plants remains largely unknown. Invertase-mediated sucrose cleavage into hexoses is central to fuel growth. Why some cytoplasmic invertases (CINs) function in the cytosol, whereas others operate in chloroplasts and mitochondria, is puzzling. We attempted to shed light on this question from an evolutionary perspective. Our analyses indicated that plant CINs originated from an putatively orthologous ancestral gene in cyanobacteria and formed the plastidic CIN (α1 clade) through endo-symbiotic gene transfer, while its duplication in algae with a loss of its signal peptide produced the β clade CINs in the cytosol. The mitochondrial CINs (α2) derived from duplication of the plastidic CINs and co-evolved with vascular plants. Importantly, the copy number of mitochondrial and plastidic CINs increased upon the emergence of seed plants, corresponding with the rise of respiratory, photosynthetic and growth rates. The cytosolic CIN (β subfamily) kept expanding from algae to gymnosperm, indicating its role in supporting the increase in carbon use efficiency during evolution. Affinity purification mass spectrometry identified a cohort of proteins interacting with α1 and 2 CINs, which points to their roles in plastid and mitochondrial glycolysis, oxidative stress tolerance and the maintenance of subcellular sugar homeostasis. Collectively, the findings indicate evolutionary roles of α1 and α2 CINs in chloroplasts and mitochondria for achieving high photosynthetic and respiratory rates, respectively, which, together with the expanding of cytosolic CINs, likely underpin the colonization of land plants through fueling rapid growth and biomass production.

RevDate: 2023-05-29
CmpDate: 2023-05-29

Rossi F, Picone G, Cappadone C, et al (2023)

Shedding Light on Osteosarcoma Cell Differentiation: Impact on Biomineralization and Mitochondria Morphology.

International journal of molecular sciences, 24(10):.

Osteosarcoma (OS) is the most common primary malignant bone tumor and its etiology has recently been associated with osteogenic differentiation dysfunctions. OS cells keep a capacity for uncontrolled proliferation showing a phenotype similar to undifferentiated osteoprogenitors with abnormal biomineralization. Within this context, both conventional and X-ray synchrotron-based techniques have been exploited to deeply characterize the genesis and evolution of mineral depositions in a human OS cell line (SaOS-2) exposed to an osteogenic cocktail for 4 and 10 days. A partial restoration of the physiological biomineralization, culminating with the formation of hydroxyapatite, was observed at 10 days after treatment together with a mitochondria-driven mechanism for calcium transportation within the cell. Interestingly, during differentiation, mitochondria showed a change in morphology from elongated to rounded, indicating a metabolic reprogramming of OS cells possibly linked to an increase in glycolysis contribution to energy metabolism. These findings add a dowel to the genesis of OS giving new insights on the development of therapeutic strategies able to restore the physiological mineralization in OS cells.

RevDate: 2023-05-25
CmpDate: 2023-05-24

Metcalfe NB, Bellman J, Bize P, et al (2023)

Solving the conundrum of intra-specific variation in metabolic rate: A multidisciplinary conceptual and methodological toolkit: New technical developments are opening the door to an understanding of why metabolic rate varies among individual animals of a species: New technical developments are opening the door to an understanding of why metabolic rate varies among individual animals of a species.

BioEssays : news and reviews in molecular, cellular and developmental biology, 45(6):e2300026.

Researchers from diverse disciplines, including organismal and cellular physiology, sports science, human nutrition, evolution and ecology, have sought to understand the causes and consequences of the surprising variation in metabolic rate found among and within individual animals of the same species. Research in this area has been hampered by differences in approach, terminology and methodology, and the context in which measurements are made. Recent advances provide important opportunities to identify and address the key questions in the field. By bringing together researchers from different areas of biology and biomedicine, we describe and evaluate these developments and the insights they could yield, highlighting the need for more standardisation across disciplines. We conclude with a list of important questions that can now be addressed by developing a common conceptual and methodological toolkit for studies on metabolic variation in animals.

RevDate: 2023-03-30
CmpDate: 2023-03-09

García Pascual B, Nordbotten JM, IG Johnston (2023)

Cellular and environmental dynamics influence species-specific extents of organelle gene retention.

Proceedings. Biological sciences, 290(1994):20222140.

Mitochondria and plastids rely on many nuclear-encoded genes, but retain small subsets of the genes they need to function in their own organelle DNA (oDNA). Different species retain different numbers of oDNA genes, and the reasons for these differences are not completely understood. Here, we use a mathematical model to explore the hypothesis that the energetic demands imposed by an organism's changing environment influence how many oDNA genes it retains. The model couples the physical biology of cell processes of gene expression and transport to a supply-and-demand model for the environmental dynamics to which an organism is exposed. The trade-off between fulfilling metabolic and bioenergetic environmental demands, and retaining genetic integrity, is quantified for a generic gene encoded either in oDNA or in nuclear DNA. Species in environments with high-amplitude, intermediate-frequency oscillations are predicted to retain the most organelle genes, whereas those in less dynamic or noisy environments the fewest. We discuss support for, and insight from, these predictions with oDNA data across eukaryotic taxa, including high oDNA gene counts in sessile organisms exposed to day-night and intertidal oscillations (including plants and algae) and low counts in parasites and fungi.

RevDate: 2023-04-01
CmpDate: 2023-02-22

Dong LF, Rohlena J, Zobalova R, et al (2023)

Mitochondria on the move: Horizontal mitochondrial transfer in disease and health.

The Journal of cell biology, 222(3):.

Mammalian genes were long thought to be constrained within somatic cells in most cell types. This concept was challenged recently when cellular organelles including mitochondria were shown to move between mammalian cells in culture via cytoplasmic bridges. Recent research in animals indicates transfer of mitochondria in cancer and during lung injury in vivo, with considerable functional consequences. Since these pioneering discoveries, many studies have confirmed horizontal mitochondrial transfer (HMT) in vivo, and its functional characteristics and consequences have been described. Additional support for this phenomenon has come from phylogenetic studies. Apparently, mitochondrial trafficking between cells occurs more frequently than previously thought and contributes to diverse processes including bioenergetic crosstalk and homeostasis, disease treatment and recovery, and development of resistance to cancer therapy. Here we highlight current knowledge of HMT between cells, focusing primarily on in vivo systems, and contend that this process is not only (patho)physiologically relevant, but also can be exploited for the design of novel therapeutic approaches.

RevDate: 2023-04-03
CmpDate: 2023-03-27

Sokolova IM (2023)

Ectotherm mitochondrial economy and responses to global warming.

Acta physiologica (Oxford, England), 237(4):e13950.

Temperature is a key abiotic factor affecting ecology, biogeography, and evolution of species. Alterations of energy metabolism play an important role in adaptations and plastic responses to temperature shifts on different time scales. Mitochondrial metabolism affects cellular bioenergetics and redox balance making these organelles an important determinant of organismal performances such as growth, locomotion, or development. Here I analyze the impacts of environmental temperature on the mitochondrial functions (including oxidative phosphorylation, proton leak, production of reactive oxygen species(ROS), and ATP synthesis) of ectotherms and discuss the mechanisms underlying negative shifts in the mitochondrial energy economy caused by supraoptimal temperatures. Owing to the differences in the thermal sensitivity of different mitochondrial processes, elevated temperatures (beyond the species- and population-specific optimal range) cause reallocation of the electron flux and the protonmotive force (Δp) in a way that decreases ATP synthesis efficiency, elevates the relative cost of the mitochondrial maintenance, causes excessive production of ROS and raises energy cost for antioxidant defense. These shifts in the mitochondrial energy economy might have negative consequences for the organismal fitness traits such as the thermal tolerance or growth. Correlation between the thermal sensitivity indices of the mitochondria and the whole organism indicate that these traits experience similar selective pressures but further investigations are needed to establish whether there is a cause-effect relationship between the mitochondrial failure and loss of organismal performance during temperature change.

RevDate: 2023-04-28
CmpDate: 2023-02-08

Zhang Y, Li W, Bian Y, et al (2023)

Multifaceted roles of aerobic glycolysis and oxidative phosphorylation in hepatocellular carcinoma.

PeerJ, 11:e14797.

Liver cancer is a common malignancy with high morbidity and mortality rates. Changes in liver metabolism are key factors in the development of primary hepatic carcinoma, and mitochondrial dysfunction is closely related to the occurrence and development of tumours. Accordingly, the study of the metabolic mechanism of mitochondria in primary hepatic carcinomas has gained increasing attention. A growing body of research suggests that defects in mitochondrial respiration are not generally responsible for aerobic glycolysis, nor are they typically selected during tumour evolution. Conversely, the dysfunction of mitochondrial oxidative phosphorylation (OXPHOS) may promote the proliferation, metastasis, and invasion of primary hepatic carcinoma. This review presents the current paradigm of the roles of aerobic glycolysis and OXPHOS in the occurrence and development of hepatocellular carcinoma (HCC). Mitochondrial OXPHOS and cytoplasmic glycolysis cooperate to maintain the energy balance in HCC cells. Our study provides evidence for the targeting of mitochondrial metabolism as a potential therapy for HCC.

RevDate: 2023-03-09
CmpDate: 2023-02-06

Muñoz-Gómez SA (2023)

Energetics and evolution of anaerobic microbial eukaryotes.

Nature microbiology, 8(2):197-203.

Mitochondria and aerobic respiration have been suggested to be required for the evolution of eukaryotic cell complexity. Aerobic respiration is several times more energetically efficient than fermentation. Moreover, aerobic respiration occurs at internalized mitochondrial membranes that are not constrained by a sublinear scaling with cell volume. However, diverse and complex anaerobic eukaryotes (for example, free-living and parasitic unicellular, and even small multicellular, eukaryotes) that exclusively rely on fermentation for energy generation have evolved repeatedly from aerobic ancestors. How do fermenting eukaryotes maintain their cell volumes and complexity while relying on such a low energy-yielding process? Here I propose that reduced rates of ATP generation in fermenting versus respiring eukaryotes are compensated for by longer cell cycles that satisfy lifetime energy demands. A literature survey and growth efficiency calculations show that fermenting eukaryotes divide approximately four to six times slower than aerobically respiring counterparts with similar cell volumes. Although ecological advantages such as competition avoidance offset lower growth rates and yields in the short term, fermenting eukaryotes inevitably have fewer physiological and ecological possibilities, which ultimately constrain their long-term evolutionary trajectories.

RevDate: 2023-04-12
CmpDate: 2023-02-08

Osipova E, Barsacchi R, Brown T, et al (2023)

Loss of a gluconeogenic muscle enzyme contributed to adaptive metabolic traits in hummingbirds.

Science (New York, N.Y.), 379(6628):185-190.

Hummingbirds possess distinct metabolic adaptations to fuel their energy-demanding hovering flight, but the underlying genomic changes are largely unknown. Here, we generated a chromosome-level genome assembly of the long-tailed hermit and screened for genes that have been specifically inactivated in the ancestral hummingbird lineage. We discovered that FBP2 (fructose-bisphosphatase 2), which encodes a gluconeogenic muscle enzyme, was lost during a time period when hovering flight evolved. We show that FBP2 knockdown in an avian muscle cell line up-regulates glycolysis and enhances mitochondrial respiration, coincident with an increased mitochondria number. Furthermore, genes involved in mitochondrial respiration and organization have up-regulated expression in hummingbird flight muscle. Together, these results suggest that FBP2 loss was likely a key step in the evolution of metabolic muscle adaptations required for true hovering flight.

RevDate: 2023-04-29
CmpDate: 2023-02-08

He L, A Maheshwari (2023)

Mitochondria in Early Life.

Current pediatric reviews, 19(4):395-416.

Mitochondria are highly-dynamic, membrane-bound organelles that generate most of the chemical energy needed to power the biochemical reactions in eukaryotic cells. These organelles also communicate with the nucleus and other cellular structures to help maintain somatic homeostasis, allow cellular adaptation to stress, and help maintain the developmental trajectory. Mitochondria also perform numerous other functions to support metabolic, energetic, and epigenetic regulation in our cells. There is increasing information on various disorders caused by defects in intrinsic mitochondrial or supporting nuclear genes, on different organ systems. In this review, we have summarized the ultrastructural morphology, structural components, our current understanding of the evolution, biogenesis, dynamics, function, clinical manifestations of mitochondrial dysfunction, and future possibilities. The implications of deficits in mitochondrial dynamics and signaling for embryo viability and offspring health are also explored. We present information from our own clinical and laboratory research in conjunction with information collected from an extensive search in the databases PubMed, EMBASE, and Scopus.

RevDate: 2022-12-21

Hogg DW, Reid AL, Dodsworth TL, et al (2022)

Skeletal muscle metabolism and contraction performance regulation by teneurin C-terminal-associated peptide-1.

Frontiers in physiology, 13:1031264.

Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The genes of two essential proteins, teneurins and latrophilins (LPHN), evolving in ancestors of multicellular animals form a ligand-receptor pair, and are now shown to be required for skeletal muscle function. Teneurins possess a bioactive peptide, termed the teneurin C-terminal associated peptide (TCAP) that interacts with the LPHNs to regulate skeletal muscle contractility strength and fatigue by an insulin-independent glucose importation mechanism in rats. CRISPR-based knockouts and siRNA-associated knockdowns of LPHN-1 and-3 in the C2C12 mouse skeletal cell line shows that TCAP stimulates an LPHN-dependent cytosolic Ca[2+] signal transduction cascade to increase energy metabolism and enhance skeletal muscle function via increases in type-1 oxidative fiber formation and reduce the fatigue response. Thus, the teneurin/TCAP-LPHN system is presented as a novel mechanism that regulates the energy requirements and performance of skeletal muscle.

RevDate: 2023-02-24
CmpDate: 2022-12-21

Mencía M (2023)

Acid digestion and symbiont: Proton sharing at the origin of mitochondriogenesis?: Proton production by a symbiotic bacterium may have been the origin of two hallmark eukaryotic features, acid digestion and mitochondria: Proton production by a symbiotic bacterium may have been the origin of two hallmark eukaryotic features, acid digestion and mitochondria.

BioEssays : news and reviews in molecular, cellular and developmental biology, 45(1):e2200136.

The initial relationships between organisms leading to endosymbiosis and the first eukaryote are currently a topic of hot debate. Here, I present a theory that offers a gradual scenario in which the origins of phagocytosis and mitochondria are intertwined in such a way that the evolution of one would not be possible without the other. In this scenario, the premitochondrial bacterial symbiont became initially associated with a protophagocytic host on the basis of cooperation to kill prey with symbiont-produced toxins and reactive oxygen species (ROS). Subsequently, the cooperation was focused on the digestion stage, through the acidification of the protophagocytic cavities via exportation of protons produced by the aerobic respiration of the symbiont. The host gained an improved phagocytic capacity and the symbiont received organic compounds from prey. As the host gradually lost its membrane energetics to develop lysosomal digestion, respiration was centralized in the premitochondrial symbiont for energy production for the consortium.

RevDate: 2022-11-16
CmpDate: 2022-11-14

Raval PK, Garg SG, SB Gould (2022)

Endosymbiotic selective pressure at the origin of eukaryotic cell biology.

eLife, 11:.

The dichotomy that separates prokaryotic from eukaryotic cells runs deep. The transition from pro- to eukaryote evolution is poorly understood due to a lack of reliable intermediate forms and definitions regarding the nature of the first host that could no longer be considered a prokaryote, the first eukaryotic common ancestor, FECA. The last eukaryotic common ancestor, LECA, was a complex cell that united all traits characterising eukaryotic biology including a mitochondrion. The role of the endosymbiotic organelle in this radical transition towards complex life forms is, however, sometimes questioned. In particular the discovery of the asgard archaea has stimulated discussions regarding the pre-endosymbiotic complexity of FECA. Here we review differences and similarities among models that view eukaryotic traits as isolated coincidental events in asgard archaeal evolution or, on the contrary, as a result of and in response to endosymbiosis. Inspecting eukaryotic traits from the perspective of the endosymbiont uncovers that eukaryotic cell biology can be explained as having evolved as a solution to housing a semi-autonomous organelle and why the addition of another endosymbiont, the plastid, added no extra compartments. Mitochondria provided the selective pressures for the origin (and continued maintenance) of eukaryotic cell complexity. Moreover, they also provided the energetic benefit throughout eukaryogenesis for evolving thousands of gene families unique to eukaryotes. Hence, a synthesis of the current data lets us conclude that traits such as the Golgi apparatus, the nucleus, autophagosomes, and meiosis and sex evolved as a response to the selective pressures an endosymbiont imposes.

RevDate: 2022-11-08
CmpDate: 2022-11-04

Zhao B, Gao S, Zhao M, et al (2022)

Mitochondrial genomic analyses provide new insights into the "missing" atp8 and adaptive evolution of Mytilidae.

BMC genomics, 23(1):738.

BACKGROUND: Mytilidae, also known as marine mussels, are widely distributed in the oceans worldwide. Members of Mytilidae show a tremendous range of ecological adaptions, from the species distributed in freshwater to those that inhabit in deep-sea. Mitochondria play an important role in energy metabolism, which might contribute to the adaptation of Mytilidae to different environments. In addition, some bivalve species are thought to lack the mitochondrial protein-coding gene ATP synthase F0 subunit 8. Increasing studies indicated that the absence of atp8 may be caused by annotation difficulties for atp8 gene is characterized by highly divergent, variable length.

RESULTS: In this study, the complete mitochondrial genomes of three marine mussels (Xenostrobus securis, Bathymodiolus puteoserpentis, Gigantidas vrijenhoeki) were newly assembled, with the lengths of 14,972 bp, 20,482, and 17,786 bp, respectively. We annotated atp8 in the sequences that we assembled and the sequences lacking atp8. The newly annotated atp8 sequences all have one predicted transmembrane domain, a similar hydropathy profile, as well as the C-terminal region with positively charged amino acids. Furthermore, we reconstructed the phylogenetic trees and performed positive selection analysis. The results showed that the deep-sea bathymodiolines experienced more relaxed evolutionary constraints. And signatures of positive selection were detected in nad4 of Limnoperna fortunei, which may contribute to the survival and/or thriving of this species in freshwater.

CONCLUSIONS: Our analysis supported that atp8 may not be missing in the Mytilidae. And our results provided evidence that the mitochondrial genes may contribute to the adaptation of Mytilidae to different environments.

RevDate: 2022-10-11
CmpDate: 2022-10-11

Paulino MG, Rossi PA, Venturini FP, et al (2022)

Liver dysfunction and energy storage mobilization in traíra, Hoplias malabaricus (Teleostei, Erythrinidae) induced by subchronic exposure to toxic cyanobacterial crude extract.

Environmental toxicology, 37(11):2683-2691.

Microcystins (MC) are hepatotoxic for organisms. Liver MC accumulation and structural change are intensely studied, but the functional hepatic enzymes and energy metabolism have received little attention. This study investigated the liver and hepatocyte structures and the activity of key hepatic functional enzymes with emphasis on energetic metabolism changes after subchronic fish exposure to cyanobacterial crude extract (CE) containing MC. The Neotropical erythrinid fish, Hoplias malabaricus, were exposed intraperitoneally to CE containing 100 μg MC-LR eq kg[-1] for 30 days and, thereafter, the plasma, liver, and white muscle was sampled for analyses. Liver tissue lost cellular structure organization showing round hepatocytes, hyperemia, and biliary duct obstruction. At the ultrastructural level, the mitochondria and the endoplasmic reticulum exhibited disorganization. Direct and total bilirubin increased in plasma. In the liver, the activity of acid phosphatase (ACP) increased, and the aspartate aminotransferase (AST) decreased; AST increased in plasma. Alkaline phosphatase (ALP) and alanine aminotransferase (ALT) were unchanged in the liver, muscle, and plasma. Glycogen stores and the energetic metabolites as glucose, lactate, and pyruvate decrease in the liver; pyruvate decreased in plasma and lactate decreased in muscle. Ammonia levels increased and protein concentration decreased in plasma. CE alters liver morphology by causing hepatocyte intracellular disorder, obstructive cholestasis, and dysfunction in the activity of key liver enzymes. The increasing energy demand implies glucose mobilization and metabolic adjustments maintaining protein preservation and lipid recruitment to supply the needs for detoxification allowing fish survival.

RevDate: 2023-03-02
CmpDate: 2022-09-08

Schavemaker PE, SA Muñoz-Gómez (2022)

The role of mitochondrial energetics in the origin and diversification of eukaryotes.

Nature ecology & evolution, 6(9):1307-1317.

The origin of eukaryotic cell size and complexity is often thought to have required an energy excess supplied by mitochondria. Recent observations show energy demands to scale continuously with cell volume, suggesting that eukaryotes do not have higher energetic capacity. However, respiratory membrane area scales superlinearly with the cell surface area. Furthermore, the consequences of the contrasting genomic architectures between prokaryotes and eukaryotes have not been precisely quantified. Here, we investigated (1) the factors that affect the volumes at which prokaryotes become surface area-constrained, (2) the amount of energy divested to DNA due to contrasting genomic architectures and (3) the costs and benefits of respiring symbionts. Our analyses suggest that prokaryotes are not surface area-constrained at volumes of 10[0]‒10[3] µm[3], the genomic architecture of extant eukaryotes is only slightly advantageous at genomes sizes of 10[6]‒10[7] base pairs and a larger host cell may have derived a greater advantage (lower cost) from harbouring ATP-producing symbionts. This suggests that eukaryotes first evolved without the need for mitochondria since these ranges hypothetically encompass the last eukaryotic common ancestor and its relatives. Our analyses also show that larger and faster-dividing prokaryotes would have a shortage of respiratory membrane area and divest more energy into DNA. Thus, we argue that although mitochondria may not have been required by the first eukaryotes, eukaryote diversification was ultimately dependent on mitochondria.

RevDate: 2023-01-03
CmpDate: 2022-11-29

McCall CE, Zhu X, Zabalawi M, et al (2022)

Sepsis, pyruvate, and mitochondria energy supply chain shortage.

Journal of leukocyte biology, 112(6):1509-1514.

Balancing high energy-consuming danger resistance and low energy supply of disease tolerance is a universal survival principle that often fails during sepsis. Our research supports the concept that sepsis phosphorylates and deactivates mitochondrial pyruvate dehydrogenase complex control over the tricarboxylic cycle and the electron transport chain. StimulatIng mitochondrial energetics in septic mice and human sepsis cell models can be achieved by inhibiting pyruvate dehydrogenase kinases with the pyruvate structural analog dichloroacetate. Stimulating the pyruvate dehydrogenase complex by dichloroacetate reverses a disruption in the tricarboxylic cycle that induces itaconate, a key mediator of the disease tolerance pathway. Dichloroacetate treatment increases mitochondrial respiration and ATP synthesis, decreases oxidant stress, overcomes metabolic paralysis, regenerates tissue, organ, and innate and adaptive immune cells, and doubles the survival rate in a murine model of sepsis.

RevDate: 2022-04-19
CmpDate: 2022-04-13

Kasperski A (2022)

Life Entrapped in a Network of Atavistic Attractors: How to Find a Rescue.

International journal of molecular sciences, 23(7):.

In view of unified cell bioenergetics, cell bioenergetic problems related to cell overenergization can cause excessive disturbances in current cell fate and, as a result, lead to a change of cell-fate. At the onset of the problem, cell overenergization of multicellular organisms (especially overenergization of mitochondria) is solved inter alia by activation and then stimulation of the reversible Crabtree effect by cells. Unfortunately, this apparently good solution can also lead to a much bigger problem when, despite the activation of the Crabtree effect, cell overenergization persists for a long time. In such a case, cancer transformation, along with the Warburg effect, may occur to further reduce or stop the charging of mitochondria by high-energy molecules. Understanding the phenomena of cancer transformation and cancer development has become a real challenge for humanity. To date, many models have been developed to understand cancer-related mechanisms. Nowadays, combining all these models into one coherent universal model of cancer transformation and development can be considered a new challenge. In this light, the aim of this article is to present such a potentially universal model supported by a proposed new model of cellular functionality evolution. The methods of fighting cancer resulting from unified cell bioenergetics and the two presented models are also considered.

RevDate: 2022-04-23
CmpDate: 2022-04-13

Snell TW, J Carberry (2022)

Astaxanthin Bioactivity Is Determined by Stereoisomer Composition and Extraction Method.

Nutrients, 14(7):.

Astaxanthin (ASX) is a natural product and one of the most powerful antioxidants known. It has significant effects on the metabolism of many animals, increasing fecundity, egg yolk volume, growth rates, immune responses, and disease resistance. A large part of the bioactivity of ASX is due to its targeting of mitochondria, where it inserts itself into cell membranes. Here, ASX stabilizes membranes and acts as a powerful antioxidant, protecting mitochondria from damage by reactive oxygen species (ROS). ROS are ubiquitous by-products of energy metabolism that must be tightly regulated by cells, lest they bind to and inactivate proteins, DNA and RNA, lipids, and signaling molecules. Most animals cannot synthesize ASX, so they need to acquire it in their diet. ASX is easily thermally denatured during extraction, and its high hydrophobicity limits its bioavailability. Our focus in this review is to contrast the bioactivity of different ASX stereoisomers and how extraction methods can denature ASX, compromising its bioavailability and bioactivity. We discuss the commercial sources of astaxanthin, structure of stereoisomers, relative bioavailability and bioactivity of ASX stereoisomers, mechanisms of ASX bioactivity, evolution of carotenoids, and why mitochondrial targeting makes ASX such an effective antioxidant.

RevDate: 2022-07-31
CmpDate: 2022-04-14

Treidel LA, Quintanilla Ramirez GS, Chung DJ, et al (2022)

Selection on dispersal drives evolution of metabolic capacities for energy production in female wing-polymorphic sand field crickets, Gryllus firmus.

Journal of evolutionary biology, 35(4):599-609.

Life history and metabolism covary, but the mechanisms and individual traits responsible for these linkages remain unresolved. Dispersal capability is a critical component of life history that is constrained by metabolic capacities for energy production. Conflicting relationships between metabolism and life histories may be explained by accounting for variation in dispersal and maximal metabolic rates. We used female wing-polymorphic sand field crickets, Gryllus firmus, selected either for long wings (LW, flight-capable) or short wings (SW, flightless) to test the hypothesis that selection on dispersal capability drives the evolution of metabolic capacities. While resting metabolic rates were similar, long-winged crickets reached higher maximal metabolic rates than short-winged crickets, resulting in improved running performance. We further provided insight into the mechanisms responsible for covariation between life history and metabolism by comparing mitochondrial content of tissues involved in powering locomotion and assessing the function of mitochondria isolated from long- and short-winged crickets. Our results demonstrated that larger metabolic capacities in long-winged crickets were underpinned by increases in mitochondrial content of dorsoventral flight muscle and enhanced bioenergetic capacities of mitochondria within the fat body, a tissue responsible for fuel storage and mobilization. Thus, selection on flight capability correlates with increases in maximal, but not resting metabolic rates, through modifications of tissues powering locomotion at the cellular and organelle levels. This allows organisms to meet high energetic demands of activity for life history. Dispersal capability should therefore explicitly be considered as a potential factor driving the evolution of metabolic capacities.

RevDate: 2022-03-14
CmpDate: 2022-03-14

Baratange C, Paris-Palacios S, Bonnard I, et al (2022)

Metabolic, cellular and defense responses to single and co-exposure to carbamazepine and methylmercury in Dreissena polymorpha.

Environmental pollution (Barking, Essex : 1987), 300:118933.

Carbamazepine (CBZ) and Hg are widespread and persistent micropollutants in aquatic environments. Both pollutants are known to trigger similar toxicity mechanisms, e.g. reactive oxygen species (ROS) production. Here, their effects were assessed in the zebra mussel Dreissena polymorpha, frequently used as a freshwater model in ecotoxicology and biomonitoring. Single and co-exposures to CBZ (3.9 μg L[-1]) and MeHg (280 ng L[-1]) were performed for 1 and 7 days. Metabolomics analyses evidenced that the co-exposure was the most disturbing after 7 days, reducing the amount of 25 metabolites involved in protein synthesis, energy metabolism, antioxidant response and osmoregulation, and significantly altering cells and organelles' structure supporting a reduction of functions of gills and digestive glands. CBZ alone after 7 days decreased the amount of α-aminobutyric acid and had a moderate effect on the structure of mitochondria in digestive glands. MeHg alone had no effect on mussels' metabolome, but caused a significant alteration of cells and organelles' structure in gills and digestive glands. Single exposures and the co-exposure increased antioxidant responses vs control in gills and digestive glands, without resulting in lipid peroxidation, suggesting an increased ROS production caused by both pollutants. Data globally supported that a higher number of hyperactive cells compensated cellular alterations in the digestive gland of mussels exposed to CBZ or MeHg alone, while CBZ + MeHg co-exposure overwhelmed this compensation after 7 days. Those effects were unpredictable based on cellular responses to CBZ and MeHg alone, highlighting the need to consider molecular toxicity pathways for a better anticipation of effects of pollutants in biota in complex environmental conditions.

RevDate: 2022-09-24
CmpDate: 2022-03-25

Giannotti D, Boscaro V, Husnik F, et al (2022)

The "Other" Rickettsiales: an Overview of the Family "Candidatus Midichloriaceae".

Applied and environmental microbiology, 88(6):e0243221.

The family "Candidatus Midichloriaceae" constitutes the most diverse but least studied lineage within the important order of intracellular bacteria Rickettsiales. "Candidatus Midichloriaceae" endosymbionts are found in many hosts, including terrestrial arthropods, aquatic invertebrates, and protists. Representatives of the family are not documented to be pathogenic, but some are associated with diseased fish or corals. Different genera display a range of unusual features, such as full sets of flagellar genes without visible flagella or the ability to invade host mitochondria. Since studies on "Ca. Midichloriaceae" tend to focus on the host, the family is rarely addressed as a unit, and we therefore lack a coherent picture of its diversity. Here, we provide four new midichloriaceae genomes, and we survey molecular and ecological data from the entire family. Features like genome size, ecological context, and host transitions vary considerably even among closely related midichloriaceae, suggesting a high frequency of such shifts, incomplete sampling, or both. Important functional traits involved in energy metabolism, flagella, and secretion systems were independently reduced multiple times with no obvious correspondence to host or habitat, corroborating the idea that many features of these "professional symbionts" are largely independent of host identity. Finally, despite "Ca. Midichloriaceae" being predominantly studied in ticks, our analyses show that the clade is mainly aquatic, with a few terrestrial offshoots. This highlights the importance of considering aquatic hosts, and protists in particular, when reconstructing the evolution of these endosymbionts and by extension all Rickettsiales. IMPORTANCE Among endosymbiotic bacterial lineages, few are as intensely studied as Rickettsiales, which include the causative agents of spotted fever, typhus, and anaplasmosis. However, an important subgroup called "Candidatus Midichloriaceae" receives little attention despite accounting for a third of the diversity of Rickettsiales and harboring a wide range of bacteria with unique features, like the ability to infect mitochondria. Midichloriaceae are found in many hosts, from ticks to corals to unicellular protozoa, and studies on them tend to focus on the host groups. Here, for the first time since the establishment of this clade, we address the genomics, evolution, and ecology of "Ca. Midichloriaceae" as a whole, highlighting trends and patterns, the remaining gaps in our knowledge, and its importance for the understanding of symbiotic processes in intracellular bacteria.

RevDate: 2022-03-21
CmpDate: 2022-03-21

Huisman TAGM, Kralik SF, Desai NK, et al (2022)

Neuroimaging of primary mitochondrial disorders in children: A review.

Journal of neuroimaging : official journal of the American Society of Neuroimaging, 32(2):191-200.

Mitochondrial disorders represent a diverse and complex group of entities typified by defective energy metabolism. The mitochondrial oxidative phosphorylation system is typically impaired, which is the predominant source of energy production. Because mitochondria are present in nearly all organs, multiple systems may be affected including the central nervous system, skeletal muscles, kidneys, and liver. In particular, those organs that are metabolically active with high energy demands are explicitly vulnerable. Initial diagnostic work up relies on a detailed evaluation of clinical symptoms including physical examination as well as a comprehensive review of the evolution of symptoms over time, relation to possible "triggering" events (eg, fever, infection), blood workup, and family history. High-end neuroimaging plays a pivotal role in establishing diagnosis, narrowing differential diagnosis, monitoring disease progression, and predicting prognosis. The pattern and characteristics of the neuroimaging findings are often highly suggestive of a mitochondrial disorder; unfortunately, in many cases the wide variability of involved metabolic processes prevents a more specific subclassification. Consequently, additional diagnostic steps including muscle biopsy, metabolic workup, and genetic tests are necessary. In the current manuscript, basic concepts of energy production, genetics, and inheritance patterns are reviewed. In addition, the imaging findings of several illustrative mitochondrial disorders are presented to familiarize the involved physicians with pediatric mitochondrial disorders. In addition, the significance of spinal cord imaging and the value of "reversed image-based discovery" for the recognition and correct (re-)classification of mitochondrial disorders is discussed.

RevDate: 2022-03-14
CmpDate: 2022-03-14

Kelly S (2021)

The economics of organellar gene loss and endosymbiotic gene transfer.

Genome biology, 22(1):345.

BACKGROUND: The endosymbiosis of the bacterial progenitors of the mitochondrion and the chloroplast are landmark events in the evolution of life on Earth. While both organelles have retained substantial proteomic and biochemical complexity, this complexity is not reflected in the content of their genomes. Instead, the organellar genomes encode fewer than 5% of the genes found in living relatives of their ancestors. While many of the 95% of missing organellar genes have been discarded, others have been transferred to the host nuclear genome through a process known as endosymbiotic gene transfer.

RESULTS: Here, we demonstrate that the difference in the per-cell copy number of the organellar and nuclear genomes presents an energetic incentive to the cell to either delete organellar genes or transfer them to the nuclear genome. We show that, for the majority of transferred organellar genes, the energy saved by nuclear transfer exceeds the costs incurred from importing the encoded protein into the organelle where it can provide its function. Finally, we show that the net energy saved by endosymbiotic gene transfer can constitute an appreciable proportion of total cellular energy budgets and is therefore sufficient to impart a selectable advantage to the cell.

CONCLUSION: Thus, reduced cellular cost and improved energy efficiency likely played a role in the reductive evolution of mitochondrial and chloroplast genomes and the transfer of organellar genes to the nuclear genome.

RevDate: 2023-02-09
CmpDate: 2022-01-06

Guberovic I, Hurtado-Bagès S, Rivera-Casas C, et al (2021)

Evolution of a histone variant involved in compartmental regulation of NAD metabolism.

Nature structural & molecular biology, 28(12):1009-1019.

NAD metabolism is essential for all forms of life. Compartmental regulation of NAD[+] consumption, especially between the nucleus and the mitochondria, is required for energy homeostasis. However, how compartmental regulation evolved remains unclear. In the present study, we investigated the evolution of the macrodomain-containing histone variant macroH2A1.1, an integral chromatin component that limits nuclear NAD[+] consumption by inhibiting poly(ADP-ribose) polymerase 1 in vertebrate cells. We found that macroH2A originated in premetazoan protists. The crystal structure of the macroH2A macrodomain from the protist Capsaspora owczarzaki allowed us to identify highly conserved principles of ligand binding and pinpoint key residue substitutions, selected for during the evolution of the vertebrate stem lineage. Metabolic characterization of the Capsaspora lifecycle suggested that the metabolic function of macroH2A was associated with nonproliferative stages. Taken together, we provide insight into the evolution of a chromatin element involved in compartmental NAD regulation, relevant for understanding its metabolism and potential therapeutic applications.

RevDate: 2023-02-09
CmpDate: 2022-01-03

Vowinckel J, Hartl J, Marx H, et al (2021)

The metabolic growth limitations of petite cells lacking the mitochondrial genome.

Nature metabolism, 3(11):1521-1535.

Eukaryotic cells can survive the loss of their mitochondrial genome, but consequently suffer from severe growth defects. 'Petite yeasts', characterized by mitochondrial genome loss, are instrumental for studying mitochondrial function and physiology. However, the molecular cause of their reduced growth rate remains an open question. Here we show that petite cells suffer from an insufficient capacity to synthesize glutamate, glutamine, leucine and arginine, negatively impacting their growth. Using a combination of molecular genetics and omics approaches, we demonstrate the evolution of fast growth overcomes these amino acid deficiencies, by alleviating a perturbation in mitochondrial iron metabolism and by restoring a defect in the mitochondrial tricarboxylic acid cycle, caused by aconitase inhibition. Our results hence explain the slow growth of mitochondrial genome-deficient cells with a partial auxotrophy in four amino acids that results from distorted iron metabolism and an inhibited tricarboxylic acid cycle.

RevDate: 2022-09-17
CmpDate: 2021-10-15

Trefts E, RJ Shaw (2021)

AMPK: restoring metabolic homeostasis over space and time.

Molecular cell, 81(18):3677-3690.

The evolution of AMPK and its homologs enabled exquisite responsivity and control of cellular energetic homeostasis. Recent work has been critical in establishing the mechanisms that determine AMPK activity, novel targets of AMPK action, and the distribution of AMPK-mediated control networks across the cellular landscape. The role of AMPK as a hub of metabolic control has led to intense interest in pharmacologic activation as a therapeutic avenue for a number of disease states, including obesity, diabetes, and cancer. As such, critical work on the compartmentalization of AMPK, its downstream targets, and the systems it influences has progressed in recent years. The variegated distribution of AMPK-mediated control of metabolic homeostasis has revealed key insights into AMPK in normal biology and future directions for AMPK-based therapeutic strategies.

RevDate: 2022-01-28
CmpDate: 2022-01-28

Jakovlić I, Zou H, Chen JH, et al (2021)

Slow crabs - fast genomes: Locomotory capacity predicts skew magnitude in crustacean mitogenomes.

Molecular ecology, 30(21):5488-5502.

Base composition skews (G-C/G+C) of mitochondrial genomes are believed to be primarily driven by mutational pressure, which is positively correlated with metabolic rate. In marine animals, metabolic rate is also positively correlated with locomotory capacity. Given the central role of mitochondria in energy metabolism, we hypothesised that selection for locomotory capacity should be positively correlated with the strength of purifying selection (dN/dS), and thus be negatively correlated with the skew magnitude. Therefore, these two models assume diametrically opposite associations between the metabolic rate and skew magnitude: positive correlation in the prevailing paradigm, and negative in our working hypothesis. We examined correlations between the skew magnitude, metabolic rate, locomotory capacity, and several other variables previously associated with mitochondrial evolution on 287 crustacean mitogenomes. Weakly locomotory taxa had higher skew magnitude and ω (dN/dS) values, but not the gene order rearrangement rate. Skew and ω magnitudes were correlated. Multilevel regression analyses indicated that three competing variables, body size, gene order rearrangement rate, and effective population size, had negligible impacts on the skew magnitude. In most crustacean lineages selection for locomotory capacity appears to be the primary factor determining the skew magnitude. Contrary to the prevailing paradigm, this implies that adaptive selection outweighs nonadaptive selection (mutation pressure) in crustaceans. However, we found indications that effective population size (nonadaptive factor) may outweigh the impact of locomotory capacity in sessile crustaceans (Thecostraca). In conclusion, skew magnitude is a product of the interplay between adaptive and nonadaptive factors, the balance of which varies among lineages.

RevDate: 2022-01-03
CmpDate: 2022-01-03

Aboouf MA, Armbruster J, Thiersch M, et al (2021)

Myoglobin, expressed in brown adipose tissue of mice, regulates the content and activity of mitochondria and lipid droplets.

Biochimica et biophysica acta. Molecular and cell biology of lipids, 1866(12):159026.

The identification of novel physiological regulators that stimulate energy expenditure through brown adipose tissue (BAT) activity in substrate catalysis is of utmost importance to understand and treat metabolic diseases. Myoglobin (MB), known to store or transport oxygen in heart and skeletal muscles, has recently been found to bind fatty acids with physiological constants in its oxygenated form (i.e., MBO2). Here, we investigated the in vivo effect of MB expression on BAT activity. In particular, we studied mitochondrial function and lipid metabolism as essential determinants of energy expenditure in this tissue. We show in a MB-null (MBko) mouse model that MB expression in BAT impacts on the activity of brown adipocytes in a twofold manner: i) by elevating mitochondrial density plus maximal respiration capacity, and through that, by stimulating BAT oxidative metabolism along with the organelles` uncoupled respiration; and ii) by influencing the free fatty acids pool towards a palmitate-enriched composition and shifting the lipid droplet (LD) equilibrium towards higher counts of smaller droplets. These metabolic changes were accompanied by the up-regulated expression of thermogenesis markers UCP1, CIDEA, CIDEC, PGC1-α and PPAR-α in the BAT of MB wildtype (MBwt) mice. Along with the emergence of the "browning" BAT morphology, MBwt mice exhibited a leaner phenotype when compared to MBko littermates at 20 weeks of age. Our data shed novel insights into MB's role in linking oxygen and lipid-based thermogenic metabolism. The findings suggest potential new strategies of targeting the MB pathway to treat metabolic disorders related to diminishing energy expenditure.

RevDate: 2021-10-18
CmpDate: 2021-10-18

Yap KN, Y Zhang (2021)

Revisiting the question of nucleated versus enucleated erythrocytes in birds and mammals.

American journal of physiology. Regulatory, integrative and comparative physiology, 321(4):R547-R557.

Erythrocyte enucleation is thought to have evolved in mammals to support their energetic cost of high metabolic activities. However, birds face similar selection pressure yet possess nucleated erythrocytes. Current hypotheses on the mammalian erythrocyte enucleation claim that the absence of cell organelles allows erythrocytes to 1) pack more hemoglobin into the cells to increase oxygen carrying capacity and 2) decrease erythrocyte size for increased surface area-to-volume ratio, and improved ability to traverse small capillaries. In this article, we first empirically tested current hypotheses using both conventional and phylogenetically informed analysis comparing literature values of mean cell hemoglobin concentration (MCHC) and mean cell volume (MCV) between 181 avian and 194 mammalian species. We found no difference in MCHC levels between birds and mammals using both conventional and phylogenetically corrected analysis. MCV was higher in birds than mammals according to conventional analysis, but the difference was lost when we controlled for phylogeny. These results suggested that avian and mammalian erythrocytes may employ different strategies to solve a common problem. To further investigate existing hypotheses or develop new hypothesis, we need to understand the functions of various organelles in avian erythrocytes. Consequently, we covered potential physiological functions of various cell organelles in avian erythrocytes based on current knowledge, while making explicit comparisons with their mammalian counterparts. Finally, we proposed by taking an integrative and comparative approach, using tools from molecular biology to evolutionary biology, would allow us to better understand the fundamental physiological functions of various components of avian and mammalian erythrocytes.

RevDate: 2021-07-01

Yang M, Dong D, X Li (2021)

The complete mitogenome of Phymorhynchus sp. (Neogastropoda, Conoidea, Raphitomidae) provides insights into the deep-sea adaptive evolution of Conoidea.

Ecology and evolution, 11(12):7518-7531.

The deep-sea environment is characterized by darkness, hypoxia, and high hydrostatic pressure. Mitochondria play a vital role in energy metabolism; thus, they may endure the selection process during the adaptive evolution of deep-sea organisms. In the present study, the mitogenome of Phymorhynchus sp. from the Haima methane seep was completely assembled and characterized. This mitogenome is 16,681 bp in length and contains 13 protein-coding genes, 2 rRNAs, and 22 tRNAs. The gene order and orientation were identical to those of most sequenced conoidean gastropods. Some special elements, such as tandem repeat sequences and AT-rich sequences, which are involved in the regulation of the replication and transcription of the mitogenome, were observed in the control region. Phylogenetic analysis revealed that Conoidea is divided into two separate clades with high nodal support. Positive selection analysis revealed evidence of adaptive changes in the mitogenomes of deep-sea conoidean gastropods. Eight residues located in atp6, cox1, cytb, nad1, nad4, and nad5 were determined to have undergone positive selection. This study explores the adaptive evolution of deep-sea conoidean gastropods and provides valuable clues at the mitochondrial level regarding the exceptional adaptive ability of organisms in deep-sea environments.

RevDate: 2022-01-28
CmpDate: 2022-01-28

Manoj KM, NM Bazhin (2021)

The murburn precepts for aerobic respiration and redox homeostasis.

Progress in biophysics and molecular biology, 167:104-120.

Murburn concept is a new perspective to metabolism which posits that certain redox enzymes/proteins mediate catalysis outside their active site, via diffusible reactive oxygen species (DROS, usually deemed as toxic wastes). We have recently questioned the proton-centric chemiosmotic rotary ATP synthesis (CRAS) explanation for mitochondrial oxidative phosphorylation (mOxPhos) and proposed an oxygen-centric murburn model in lieu. Herein, the chemical equations and thermodynamic foundations for this new model of mOxPhos are detailed. Standard transformed Gibbs free energy values of respiratory reactions are calculated to address the spontaneity, control, and efficiency of oxidative phosphorylation. Unlike the deterministic/multi-molecular and 'irreducibly complex' CRAS model, the stochastic/bimolecular and parsimonious murburn reactions afford a more viable precept for the variable and non-integral stoichiometry, higher yield for NADH than FADH2, and origin/evolution of oxygen-centric cellular life. Also, we present tangible DROS-based explanations for the multiple roles of various reaction components, HCN > H2S order of cellular toxicity in aerobes, and explain why oxygen inhibits anaerobes. We highlight the thermodynamic significance of proton deficiency in NADH/mitochondria and link the 'oxygen → DROS → water' metabolic pathway to the macroscopic physiologies of ATP-synthesis, trans-membrane potential, thermogenesis, and homeostasis. We also provide arguments for the extension of the murburn bioenergetics model to life under anoxic and extreme/unique habitats. In the context of mOxPhos, our findings imply that DROS should be seen as an essential requisite for life, and not merely as pathophysiological manifestations.

RevDate: 2022-03-24
CmpDate: 2022-03-24

Spinelli S, Begani G, Guida L, et al (2021)

LANCL1 binds abscisic acid and stimulates glucose transport and mitochondrial respiration in muscle cells via the AMPK/PGC-1α/Sirt1 pathway.

Molecular metabolism, 53:101263.

OBJECTIVE: Abscisic acid (ABA) is a plant hormone also present and active in animals. In mammals, ABA regulates blood glucose levels by stimulating insulin-independent glucose uptake and metabolism in adipocytes and myocytes through its receptor LANCL2. The objective of this study was to investigate whether another member of the LANCL protein family, LANCL1, also behaves as an ABA receptor and, if so, which functional effects are mediated by LANCL1.

METHODS: ABA binding to human recombinant LANCL1 was explored by equilibrium-binding experiments with [[3]H]ABA, circular dichroism, and surface plasmon resonance. Rat L6 myoblasts overexpressing either LANCL1 or LANCL2, or silenced for the expression of both proteins, were used to investigate the basal and ABA-stimulated transport of a fluorescent glucose analog (NBDG) and the signaling pathway downstream of the LANCL proteins using Western blot and qPCR analysis. Finally, glucose tolerance and sensitivity to ABA were compared in LANCL2[-/-] and wild-type (WT) siblings.

RESULTS: Human recombinant LANCL1 binds ABA with a Kd between 1 and 10 μM, depending on the assay (i.e., in a concentration range that lies between the low and high-affinity ABA binding sites of LANCL2). In L6 myoblasts, LANCL1 and LANCL2 similarly, i) stimulate both basal and ABA-triggered NBDG uptake (4-fold), ii) activate the transcription and protein expression of the glucose transporters GLUT4 and GLUT1 (4-6-fold) and the signaling proteins AMPK/PGC-1α/Sirt1 (2-fold), iii) stimulate mitochondrial respiration (5-fold) and the expression of the skeletal muscle (SM) uncoupling proteins sarcolipin (3-fold) and UCP3 (12-fold). LANCL2[-/-] mice have a reduced glucose tolerance compared to WT. They spontaneously overexpress LANCL1 in the SM and respond to chronic ABA treatment (1 μg/kg body weight/day) with an improved glycemia response to glucose load and an increased SM transcription of GLUT4 and GLUT1 (20-fold) of the AMPK/PGC-1α/Sirt1 pathway and sarcolipin, UCP3, and NAMPT (4- to 6-fold).

CONCLUSIONS: LANCL1 behaves as an ABA receptor with a somewhat lower affinity for ABA than LANCL2 but with overlapping effector functions: stimulating glucose uptake and the expression of muscle glucose transporters and mitochondrial uncoupling and respiration via the AMPK/PGC-1α/Sirt1 pathway. Receptor redundancy may have been advantageous in animal evolution, given the role of the ABA/LANCL system in the insulin-independent stimulation of cell glucose uptake and energy metabolism.

RevDate: 2022-03-04
CmpDate: 2022-03-04

Mathur V, Wakeman KC, PJ Keeling (2021)

Parallel functional reduction in the mitochondria of apicomplexan parasites.

Current biology : CB, 31(13):2920-2928.e4.

Gregarines are an early-diverging lineage of apicomplexan parasites that hold many clues into the origin and evolution of the group, a remarkable transition from free-living phototrophic algae into obligate parasites of animals.[1] Using single-cell transcriptomics targeting understudied lineages to complement available sequencing data, we characterized the mitochondrial metabolic repertoire across the tree of apicomplexans. In contrast to the large suite of proteins involved in aerobic respiration in well-studied parasites like Toxoplasma or Plasmodium,[2] we find that gregarine trophozoites have significantly reduced energy metabolism: most lack respiratory complexes III and IV, and some lack the electron transport chains (ETCs) and tricarboxylic acid (TCA) cycle entirely. Phylogenomic analyses show that these reductions took place several times in parallel, resulting in a functional range from fully aerobic organelles to extremely reduced "mitosomes" restricted to Fe-S cluster biosynthesis. The mitochondrial genome has also been lost repeatedly: in species with severe functional reduction simply by gene loss but in one species with a complete ETC by relocating cox1 to the nuclear genome. Severe functional reduction of mitochondria is generally associated with structural reduction, resulting in small, nondescript mitochondrial-related organelles (MROs).[3] By contrast, gregarines retain distinctive mitochondria with tubular cristae, even the most functionally reduced cases that also lack genes associated with cristae formation. Overall, the parallel, severe reduction of gregarine mitochondria expands the diversity of organisms that contain MROs and further emphasizes the role of parallel transitions in apicomplexan evolution.

RevDate: 2021-12-14
CmpDate: 2021-12-03

Salomaki ED, Terpis KX, Rueckert S, et al (2021)

Gregarine single-cell transcriptomics reveals differential mitochondrial remodeling and adaptation in apicomplexans.

BMC biology, 19(1):77.

BACKGROUND: Apicomplexa is a diverse phylum comprising unicellular endobiotic animal parasites and contains some of the most well-studied microbial eukaryotes including the devastating human pathogens Plasmodium falciparum and Cryptosporidium hominis. In contrast, data on the invertebrate-infecting gregarines remains sparse and their evolutionary relationship to other apicomplexans remains obscure. Most apicomplexans retain a highly modified plastid, while their mitochondria remain metabolically conserved. Cryptosporidium spp. inhabit an anaerobic host-gut environment and represent the known exception, having completely lost their plastid while retaining an extremely reduced mitochondrion that has lost its genome. Recent advances in single-cell sequencing have enabled the first broad genome-scale explorations of gregarines, providing evidence of differential plastid retention throughout the group. However, little is known about the retention and metabolic capacity of gregarine mitochondria.

RESULTS: Here, we sequenced transcriptomes from five species of gregarines isolated from cockroaches. We combined these data with those from other apicomplexans, performed detailed phylogenomic analyses, and characterized their mitochondrial metabolism. Our results support the placement of Cryptosporidium as the earliest diverging lineage of apicomplexans, which impacts our interpretation of evolutionary events within the phylum. By mapping in silico predictions of core mitochondrial pathways onto our phylogeny, we identified convergently reduced mitochondria. These data show that the electron transport chain has been independently lost three times across the phylum, twice within gregarines.

CONCLUSIONS: Apicomplexan lineages show variable functional restructuring of mitochondrial metabolism that appears to have been driven by adaptations to parasitism and anaerobiosis. Our findings indicate that apicomplexans are rife with convergent adaptations, with shared features including morphology, energy metabolism, and intracellularity.

RevDate: 2021-09-28
CmpDate: 2021-09-28

de Meeûs d'Argenteuil C, Boshuizen B, Oosterlinck M, et al (2021)

Flexibility of equine bioenergetics and muscle plasticity in response to different types of training: An integrative approach, questioning existing paradigms.

PloS one, 16(4):e0249922.

Equine bioenergetics have predominantly been studied focusing on glycogen and fatty acids. Combining omics with conventional techniques allows for an integrative approach to broadly explore and identify important biomolecules. Friesian horses were aquatrained (n = 5) or dry treadmill trained (n = 7) (8 weeks) and monitored for: evolution of muscle diameter in response to aquatraining and dry treadmill training, fiber type composition and fiber cross-sectional area of the M. pectoralis, M. vastus lateralis and M. semitendinosus and untargeted metabolomics of the M. pectoralis and M. vastus lateralis in response to dry treadmill training. Aquatraining was superior to dry treadmill training to increase muscle diameter in the hindquarters, with maximum effect after 4 weeks. After dry treadmill training, the M. pectoralis showed increased muscle diameter, more type I fibers, decreased fiber mean cross sectional area, and an upregulated oxidative metabolic profile: increased β-oxidation (key metabolites: decreased long chain fatty acids and increased long chain acylcarnitines), TCA activity (intermediates including succinyl-carnitine and 2-methylcitrate), amino acid metabolism (glutamine, aromatic amino acids, serine, urea cycle metabolites such as proline, arginine and ornithine) and xenobiotic metabolism (especially p-cresol glucuronide). The M. vastus lateralis expanded its fast twitch profile, with decreased muscle diameter, type I fibers and an upregulation of glycolytic and pentose phosphate pathway activity, and increased branched-chain and aromatic amino acid metabolism (cis-urocanate, carnosine, homocarnosine, tyrosine, tryptophan, p-cresol-glucuronide, serine, methionine, cysteine, proline and ornithine). Trained Friesians showed increased collagen and elastin turn-over. Results show that branched-chain amino acids, aromatic amino acids and microbiome-derived xenobiotics need further study in horses. They feed the TCA cycle at steps further downstream from acetyl CoA and most likely, they are oxidized in type IIA fibers, the predominant fiber type of the horse. These study results underline the importance of reviewing existing paradigms on equine bioenergetics.

RevDate: 2021-11-15
CmpDate: 2021-11-15

Ramzan R, Kadenbach B, S Vogt (2021)

Multiple Mechanisms Regulate Eukaryotic Cytochrome C Oxidase.

Cells, 10(3):.

Cytochrome c oxidase (COX), the rate-limiting enzyme of mitochondrial respiration, is regulated by various mechanisms. Its regulation by ATP (adenosine triphosphate) appears of particular importance, since it evolved early during evolution and is still found in cyanobacteria, but not in other bacteria. Therefore the "allosteric ATP inhibition of COX" is described here in more detail. Most regulatory properties of COX are related to "supernumerary" subunits, which are largely absent in bacterial COX. The "allosteric ATP inhibition of COX" was also recently described in intact isolated rat heart mitochondria.

RevDate: 2022-10-26
CmpDate: 2021-11-08

Graf JS, Schorn S, Kitzinger K, et al (2021)

Anaerobic endosymbiont generates energy for ciliate host by denitrification.

Nature, 591(7850):445-450.

Mitochondria are specialized eukaryotic organelles that have a dedicated function in oxygen respiration and energy production. They evolved about 2 billion years ago from a free-living bacterial ancestor (probably an alphaproteobacterium), in a process known as endosymbiosis[1,2]. Many unicellular eukaryotes have since adapted to life in anoxic habitats and their mitochondria have undergone further reductive evolution[3]. As a result, obligate anaerobic eukaryotes with mitochondrial remnants derive their energy mostly from fermentation[4]. Here we describe 'Candidatus Azoamicus ciliaticola', which is an obligate endosymbiont of an anaerobic ciliate and has a dedicated role in respiration and providing energy for its eukaryotic host. 'Candidatus A. ciliaticola' contains a highly reduced 0.29-Mb genome that encodes core genes for central information processing, the electron transport chain, a truncated tricarboxylic acid cycle, ATP generation and iron-sulfur cluster biosynthesis. The genome encodes a respiratory denitrification pathway instead of aerobic terminal oxidases, which enables its host to breathe nitrate instead of oxygen. 'Candidatus A. ciliaticola' and its ciliate host represent an example of a symbiosis that is based on the transfer of energy in the form of ATP, rather than nutrition. This discovery raises the possibility that eukaryotes with mitochondrial remnants may secondarily acquire energy-providing endosymbionts to complement or replace functions of their mitochondria.

RevDate: 2023-01-29
CmpDate: 2021-02-23

Uwizeye C, Decelle J, Jouneau PH, et al (2021)

Morphological bases of phytoplankton energy management and physiological responses unveiled by 3D subcellular imaging.

Nature communications, 12(1):1049.

Eukaryotic phytoplankton have a small global biomass but play major roles in primary production and climate. Despite improved understanding of phytoplankton diversity and evolution, we largely ignore the cellular bases of their environmental plasticity. By comparative 3D morphometric analysis across seven distant phytoplankton taxa, we observe constant volume occupancy by the main organelles and preserved volumetric ratios between plastids and mitochondria. We hypothesise that phytoplankton subcellular topology is modulated by energy-management constraints. Consistent with this, shifting the diatom Phaeodactylum from low to high light enhances photosynthesis and respiration, increases cell-volume occupancy by mitochondria and the plastid CO2-fixing pyrenoid, and boosts plastid-mitochondria contacts. Changes in organelle architectures and interactions also accompany Nannochloropsis acclimation to different trophic lifestyles, along with respiratory and photosynthetic responses. By revealing evolutionarily-conserved topologies of energy-managing organelles, and their role in phytoplankton acclimation, this work deciphers phytoplankton responses at subcellular scales.

RevDate: 2021-09-16
CmpDate: 2021-09-16

Subramanian V, Rodemoyer B, Shastri V, et al (2021)

Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes.

Scientific reports, 11(1):2157.

Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the Bloom syndrome DNA helicase BLM as a recombination factor in maintaining genome stability and suppressing cancer. Here, we observed increased levels of reactive oxygen species (ROS) and DNA base damage in BLM-deficient cells, as well as oxidative-stress-dependent reduction in DNA replication speed. BLM-deficient cells exhibited increased mitochondrial mass, upregulation of mitochondrial transcription factor A (TFAM), higher ATP levels and increased respiratory reserve capacity. Cyclin B1, which acts in complex with cyclin-dependent kinase CDK1 to regulate mitotic entry and associated mitochondrial fission by phosphorylating mitochondrial fission protein Drp1, fails to be fully degraded in BLM-deficient cells and shows unscheduled expression in G1 phase cells. This failure to degrade cyclin B1 is accompanied by increased levels and persistent activation of Drp1 throughout mitosis and into G1 phase as well as mitochondrial fragmentation. This study identifies mitochondria-associated abnormalities in Bloom syndrome patient-derived and BLM-knockout cells and we discuss how these abnormalities may contribute to Bloom syndrome.

RevDate: 2021-12-20
CmpDate: 2021-12-20

Pamplona R, Jové M, Mota-Martorell N, et al (2021)

Is the NDUFV2 subunit of the hydrophilic complex I domain a key determinant of animal longevity?.

The FEBS journal, 288(23):6652-6673.

Complex I, a component of the electron transport chain, plays a central functional role in cell bioenergetics and the biology of free radicals. The structural and functional N module of complex I is one of the main sites of the generation of free radicals. The NDUFV2 subunit/N1a cluster is a component of this module. Furthermore, the rate of free radical production is linked to animal longevity. In this review, we explore the hypothesis that NDUFV2 is the only conserved core subunit designed with a regulatory function to ensure correct electron transfer and free radical production, that low gene expression and protein abundance of the NDUFV2 subunit is an evolutionary adaptation needed to achieve a longevity phenotype, and that these features are determinants of the lower free radical generation at the mitochondrial level and a slower rate of aging of long-lived animals.

RevDate: 2021-11-10
CmpDate: 2021-11-10

Fuentealba M, Fabian DK, Dönertaş HM, et al (2021)

Transcriptomic profiling of long- and short-lived mutant mice implicates mitochondrial metabolism in ageing and shows signatures of normal ageing in progeroid mice.

Mechanisms of ageing and development, 194:111437.

Genetically modified mouse models of ageing are the living proof that lifespan and healthspan can be lengthened or shortened, and provide a powerful context in which to unravel the molecular mechanisms at work. In this study, we analysed and compared gene expression data from 10 long-lived and 8 short-lived mouse models of ageing. Transcriptome-wide correlation analysis revealed that mutations with equivalent effects on lifespan induce more similar transcriptomic changes, especially if they target the same pathway. Using functional enrichment analysis, we identified 58 gene sets with consistent changes in long- and short-lived mice, 55 of which were up-regulated in long-lived mice and down-regulated in short-lived mice. Half of these sets represented genes involved in energy and lipid metabolism, among which Ppargc1a, Mif, Aldh5a1 and Idh1 were frequently observed. Based on the gene sets with consistent changes, and also the whole transcriptome, the gene expression changes during normal ageing resembled the transcriptome of short-lived models, suggesting that accelerated ageing models reproduce partially the molecular changes of ageing. Finally, we identified new genetic interventions that may ameliorate ageing, by comparing the transcriptomes of 51 mouse mutants not previously associated with ageing to expression signatures of long- and short-lived mice and ageing-related changes.

RevDate: 2021-04-21
CmpDate: 2021-04-21

Koch RE, Buchanan KL, Casagrande S, et al (2021)

Integrating Mitochondrial Aerobic Metabolism into Ecology and Evolution.

Trends in ecology & evolution, 36(4):321-332.

Biologists have long appreciated the critical role that energy turnover plays in understanding variation in performance and fitness among individuals. Whole-organism metabolic studies have provided key insights into fundamental ecological and evolutionary processes. However, constraints operating at subcellular levels, such as those operating within the mitochondria, can also play important roles in optimizing metabolism over different energetic demands and time scales. Herein, we explore how mitochondrial aerobic metabolism influences different aspects of organismal performance, such as through changing adenosine triphosphate (ATP) and reactive oxygen species (ROS) production. We consider how such insights have advanced our understanding of the mechanisms underpinning key ecological and evolutionary processes, from variation in life-history traits to adaptation to changing thermal conditions, and we highlight key areas for future research.

RevDate: 2021-06-29
CmpDate: 2021-05-14

Chen C, Mahar R, Merritt ME, et al (2021)

ROS and hypoxia signaling regulate periodic metabolic arousal during insect dormancy to coordinate glucose, amino acid, and lipid metabolism.

Proceedings of the National Academy of Sciences of the United States of America, 118(1):.

Metabolic suppression is a hallmark of animal dormancy that promotes overall energy savings. Some diapausing insects and some mammalian hibernators have regular cyclic patterns of substantial metabolic depression alternating with periodic arousal where metabolic rates increase dramatically. Previous studies, largely in mammalian hibernators, have shown that periodic arousal is driven by an increase in aerobic mitochondrial metabolism and that many molecules related to energy metabolism fluctuate predictably across periodic arousal cycles. However, it is still not clear how these rapid metabolic shifts are regulated. We first found that diapausing flesh fly pupae primarily use anaerobic glycolysis during metabolic depression but engage in aerobic respiration through the tricarboxylic acid cycle during periodic arousal. Diapausing pupae also clear anaerobic by-products and regenerate many metabolic intermediates depleted in metabolic depression during arousal, consistent with patterns in mammalian hibernators. We found that decreased levels of reactive oxygen species (ROS) induced metabolic arousal and elevated ROS extended the duration of metabolic depression. Our data suggest ROS regulates the timing of metabolic arousal by changing the activity of two critical metabolic enzymes, pyruvate dehydrogenase and carnitine palmitoyltransferase I by modulating the levels of hypoxia inducible transcription factor (HIF) and phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK). Our study shows that ROS signaling regulates periodic arousal in our insect diapasue system, suggesting the possible importance ROS for regulating other types of of metabolic cycles in dormancy as well.

RevDate: 2020-12-31

Yang RS, YT Chen (2020)

The complete mitochondrial genome of the freshwater fairy shrimp Branchinella kugenumaensis Ishikawa 1894 (Crustacea: Anostraca: Thamnocephalidae).

Mitochondrial DNA. Part B, Resources, 5(1):1048-1049.

In this study, we determined and analyzed the complete mitochondrial genome of the freshwater fairy shrimp Branchinella kugenumaensis Ishikawa 1894 (Crustacea: Anostraca: Thamnocephalidae). The mitogenome is 15,127 bp in length, consisted of 37 genes that participate in protein production and energy metabolism of mitochondria. The gene order of the B. kugenumaensis mtDNA exhibits major rearrangements compared with the pancrustacean ancestral pattern or other known anostracan mitogenomes, representing a novel mitochondrial genomic organization within the Crustacea. A maximum-likelihood phylogenetic analysis based on concatenated nucleotide sequences of protein-coding genes places B. kugenumaensis next to Streptocephalus sirindhornae, inside the Anostraca clade. Our study will provide new evidence to the less sampled anostracan evolution and take a further step to the completion of the Branchiopoda tree of life.

RevDate: 2021-06-28
CmpDate: 2021-06-28

Else PL (2021)

Mammals to membranes: A reductionist story.

Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology, 253:110552.

This is the story of a series of reductionist studies that started with an attempt to explain what underpins the high-level of aerobic metabolism in mammals (i.e. associated with the evolution of endothermy) and almost forty years later had led to investigations into the role of membrane lipids in determining metabolism. Initial studies showed that the increase in aerobic metabolism in mammals was driven by a combination of increases in mitochondrial volume and membrane densities, organ size and changes in the molecular activity of enzymes. The increase in the capacity to produce energy was matched by an increase in energy use, notably driven by increases in H[+], Na[+] and K[+] fluxes. In the case of increased Na[+] flux, it was found this was matched by increases in Na[+]-dependent metabolism at the tissue level and increases in enzyme activity at a cellular level but not by an increase in the number of sodium pumps. To maintain Na[+] gradient across cell membranes, increased Na[+] flux is not controlled by an increase in sodium pump number but rather by an increase in sodium pump molecular activity (i.e. an increase the substrate turnover rate of each sodium pump) in tissues of endotherms. This increase in molecular activity is coupled to an increase in the level of highly unsaturated polyunsaturated fatty acids (PUFA) in membranes, a mechanism similar to that used by ectotherms to ameliorate decreasing activities of metabolic processes in the cold. Determination of how changes in membrane fatty acid composition can change the activities of proteins in membranes will be the next step in this story.

RevDate: 2021-01-04
CmpDate: 2021-01-04

Harshkova D, Majewska M, Pokora W, et al (2021)

Diclofenac and atrazine restrict the growth of a synchronous Chlamydomonas reinhardtii population via various mechanisms.

Aquatic toxicology (Amsterdam, Netherlands), 230:105698.

Non-steroidal anti-inflammatory drug diclofenac (DCF) is commonly found in freshwater bodies and can have adverse effects on non-target organisms. Among the studies on DCF toxicity, several ones have reported its harmful effects on plants and algae. To gain a better understanding of the mechanisms of DCF toxicity towards green algae, we used a synchronous Chlamydomonas reinhardtii cc-1690 culture and compared DCF (135 mg/L) effects with effects caused by atrazine (ATR; 77.6 μg/L), an herbicide with a well-known mechanism of toxic action. To achieve our goal, cell number and size, photosynthetic oxygen consumption/evolution, chlorophyll a fluorescence in vivo, H2O2 production by the cells, antioxidative enzymes encoding genes expression were analyzed during light phase of the cell cycle. We have found, that DCF and ATR affect C. reinhardtii through different mechanisms. ATR inhibited the photosynthetic electron transport chain and induced oxidative stress in chloroplast. Such chloroplastic energetics disruption indirectly influenced respiration, the intensification of which could partially mitigate low efficiency of photosynthetic energy production. As a result, ATR inhibited the growth of single cell leading to limitation in C. reinhardtii population development. In contrast to ATR-treated algae, in DCF-treated cells the fraction of active PSII reaction centers was diminished without drastic changes in electron transport or oxidative stress symptoms in chloroplast. However, significant increase in transcript level of gene encoding for mitochondria-located catalase indicates respiratory processes as a source of H2O2 overproduced in the DCF-treated cells. Because the single cell growth was not strongly affected by DCF, its adverse effect on progeny cell number seemed to be related rather to arresting of cell divisions. Concluding, although the DCF phytotoxic action appeared to be different from the action of the typical herbicide ATR, it can act as algal growth-inhibiting factor in the environment.

RevDate: 2022-02-02
CmpDate: 2021-10-06

Cortassa S, Juhaszova M, Aon MA, et al (2021)

Mitochondrial Ca[2+], redox environment and ROS emission in heart failure: Two sides of the same coin?.

Journal of molecular and cellular cardiology, 151:113-125.

Heart failure (HF) is a progressive, debilitating condition characterized, in part, by altered ionic equilibria, increased ROS production and impaired cellular energy metabolism, contributing to variable profiles of systolic and diastolic dysfunction with significant functional limitations and risk of premature death. We summarize current knowledge concerning changes of intracellular Na[+] and Ca[2+] control mechanisms during the disease progression and their consequences on mitochondrial Ca[2+] homeostasis and the shift in redox balance. Absent existing biological data, our computational modeling studies advance a new 'in silico' analysis to reconcile existing opposing views, based on different experimental HF models, regarding variations in mitochondrial Ca[2+] concentration that participate in triggering and perpetuating oxidative stress in the failing heart and their impact on cardiac energetics. In agreement with our hypothesis and the literature, model simulations demonstrate the possibility that the heart's redox status together with cytoplasmic Na[+] concentrations act as regulators of mitochondrial Ca[2+] levels in HF and of the bioenergetics response that will ultimately drive ATP supply and oxidative stress. The resulting model predictions propose future directions to study the evolution of HF as well as other types of heart disease, and to develop novel testable mechanistic hypotheses that may lead to improved therapeutics.

RevDate: 2021-04-27
CmpDate: 2021-04-27

Xu H, Zhou W, Zhan L, et al (2020)

The ZiBuPiYin recipe regulates proteomic alterations in brain mitochondria-associated ER membranes caused by chronic psychological stress exposure: Implications for cognitive decline in Zucker diabetic fatty rats.

Aging, 12(23):23698-23726.

Chronic psychological stress (PS) cumulatively affects memory performance through the deleterious effects on hypothalamic-pituitary-adrenal axis regulation. Several functions damaged in cognitive impairment-related diseases are regulated by mitochondria-associated ER membranes (MAMs). To elucidate the role of ZiBuPiYin recipe (ZBPYR) in regulating the MAM proteome to improve PS-induced diabetes-associated cognitive decline (PSD), differentially expressed MAM proteins were identified among Zucker diabetic fatty rats, PSD rats, and PS combined with ZBPYR administration rats via iTRAQ with LC-MS/MS. Proteomic analysis revealed that the expressions of 85 and 33 proteins were altered by PS and ZBPYR treatment, respectively. Among these, 21 proteins were differentially expressed under both PS and ZBPYR treatments, whose functional categories included energy metabolism, lipid and protein metabolism, and synaptic dysfunction. Furthermore, calcium signaling and autophagy-related proteins may play roles in the pathogenesis of PSD and the mechanism of ZBPYR, respectively. Notably, KEGG pathway analysis suggested that 'Alzheimer's disease' and 'oxidative phosphorylation' pathways may be impaired in PSD pathogenesis, while ZBPYR could play a neuroprotective role through regulating the above pathways. Overall, exposure to chronic PS contributes to the evolution of diabetes-associated cognitive decline and ZBPYR might prevent and treat PSD by regulating the MAM proteome.

RevDate: 2021-07-07
CmpDate: 2021-07-07

Lukeš J, Kaur B, D Speijer (2021)

RNA Editing in Mitochondria and Plastids: Weird and Widespread.

Trends in genetics : TIG, 37(2):99-102.

Though widespread, RNA editing is rare, except in endosymbiotic organelles. A combination of higher mutation rates, relaxation of energetic constraints, and high genetic drift is found within plastids and mitochondria and is conducive for evolution and expansion of editing processes, possibly starting as repair mechanisms. To illustrate this, we present an exhaustive phylogenetic overview of editing types.

RevDate: 2021-03-01
CmpDate: 2021-03-01

Zhu Y, Berkowitz O, Selinski J, et al (2020)

Conserved and Opposite Transcriptome Patterns during Germination in Hordeum vulgare and Arabidopsis thaliana.

International journal of molecular sciences, 21(19):.

Seed germination is a critical process for completion of the plant life cycle and for global food production. Comparing the germination transcriptomes of barley (Hordeum vulgare) to Arabidopsis thaliana revealed the overall pattern was conserved in terms of functional gene ontology; however, many oppositely responsive orthologous genes were identified. Conserved processes included a set of approximately 6000 genes that peaked early in germination and were enriched in processes associated with RNA metabolism, e.g., pentatricopeptide repeat (PPR)-containing proteins. Comparison of orthologous genes revealed more than 3000 orthogroups containing almost 4000 genes that displayed similar expression patterns including functions associated with mitochondrial tricarboxylic acid (TCA) cycle, carbohydrate and RNA/DNA metabolism, autophagy, protein modifications, and organellar function. Biochemical and proteomic analyses indicated mitochondrial biogenesis occurred early in germination, but detailed analyses revealed the timing involved in mitochondrial biogenesis may vary between species. More than 1800 orthogroups representing 2000 genes displayed opposite patterns in transcript abundance, representing functions of energy (carbohydrate) metabolism, photosynthesis, protein synthesis and degradation, and gene regulation. Differences in expression of basic-leucine zippers (bZIPs) and Apetala 2 (AP2)/ethylene-responsive element binding proteins (EREBPs) point to differences in regulatory processes at a high level, which provide opportunities to modify processes in order to enhance grain quality, germination, and storage as needed for different uses.

RevDate: 2020-12-18
CmpDate: 2020-10-22

Tan DX, R Hardeland (2020)

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19.

Molecules (Basel, Switzerland), 25(19):.

Fighting infectious diseases, particularly viral infections, is a demanding task for human health. Targeting the pathogens or targeting the host are different strategies, but with an identical purpose, i.e., to curb the pathogen's spreading and cure the illness. It appears that targeting a host to increase tolerance against pathogens can be of substantial advantage and is a strategy used in evolution. Practically, it has a broader protective spectrum than that of only targeting the specific pathogens, which differ in terms of susceptibility. Methods for host targeting applied in one pandemic can even be effective for upcoming pandemics with different pathogens. This is even more urgent if we consider the possible concomitance of two respiratory diseases with potential multi-organ afflictions such as Coronavirus disease 2019 (COVID-19) and seasonal flu. Melatonin is a molecule that can enhance the host's tolerance against pathogen invasions. Due to its antioxidant, anti-inflammatory, and immunoregulatory activities, melatonin has the capacity to reduce the severity and mortality of deadly virus infections including COVID-19. Melatonin is synthesized and functions in mitochondria, which play a critical role in viral infections. Not surprisingly, melatonin synthesis can become a target of viral strategies that manipulate the mitochondrial status. For example, a viral infection can switch energy metabolism from respiration to widely anaerobic glycolysis even if plenty of oxygen is available (the Warburg effect) when the host cell cannot generate acetyl-coenzyme A, a metabolite required for melatonin biosynthesis. Under some conditions, including aging, gender, predisposed health conditions, already compromised mitochondria, when exposed to further viral challenges, lose their capacity for producing sufficient amounts of melatonin. This leads to a reduced support of mitochondrial functions and makes these individuals more vulnerable to infectious diseases. Thus, the maintenance of mitochondrial function by melatonin supplementation can be expected to generate beneficial effects on the outcome of viral infectious diseases, particularly COVID-19.

RevDate: 2020-10-20

Karakaidos P, T Rampias (2020)

Mitonuclear Interactions in the Maintenance of Mitochondrial Integrity.

Life (Basel, Switzerland), 10(9):.

In eukaryotic cells, mitochondria originated in an α-proteobacterial endosymbiont. Although these organelles harbor their own genome, the large majority of genes, originally encoded in the endosymbiont, were either lost or transferred to the nucleus. As a consequence, mitochondria have become semi-autonomous and most of their processes require the import of nuclear-encoded components to be functional. Therefore, the mitochondrial-specific translation has evolved to be coordinated by mitonuclear interactions to respond to the energetic demands of the cell, acquiring unique and mosaic features. However, mitochondrial-DNA-encoded genes are essential for the assembly of the respiratory chain complexes. Impaired mitochondrial function due to oxidative damage and mutations has been associated with numerous human pathologies, the aging process, and cancer. In this review, we highlight the unique features of mitochondrial protein synthesis and provide a comprehensive insight into the mitonuclear crosstalk and its co-evolution, as well as the vulnerabilities of the animal mitochondrial genome.

RevDate: 2022-01-29
CmpDate: 2021-03-09

Srivastava SR, R Mahalakshmi (2020)

Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance.

The Journal of biological chemistry, 295(43):14653-14665.

Transmembrane β-barrels of eukaryotic outer mitochondrial membranes (OMMs) are major channels of communication between the cytosol and mitochondria and are indispensable for cellular homeostasis. A structurally intriguing exception to all known transmembrane β-barrels is the unique odd-stranded, i.e. 19-stranded, structures found solely in the OMM. The molecular origins of this 19-stranded structure and its associated functional significance are unclear. In humans, the most abundant OMM transporter is the voltage-dependent anion channel. Here, using the human voltage-dependent anion channel as our template scaffold, we designed and engineered odd- and even-stranded structures of smaller (V2[16], V2[17], V2[18]) and larger (V2[20], V2[21]) barrel diameters. Determination of the structure, dynamics, and energetics of these engineered structures in bilayer membranes reveals that the 19-stranded barrel surprisingly holds modest to low stability in a lipid-dependent manner. However, we demonstrate that this structurally metastable protein possesses superior voltage-gated channel regulation, efficient mitochondrial targeting, and in vivo cell survival, with lipid-modulated stability, all of which supersede the occurrence of a metastable 19-stranded scaffold. We propose that the unique structural adaptation of these transmembrane transporters exclusively in mitochondria bears strong evolutionary basis and is functionally significant for homeostasis.

RevDate: 2022-12-08
CmpDate: 2020-11-02

Cunnane SC, Trushina E, Morland C, et al (2020)

Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing.

Nature reviews. Drug discovery, 19(9):609-633.

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner - a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.

RevDate: 2022-05-31
CmpDate: 2022-04-07

Chevalier RL (2020)

Bioenergetic Evolution Explains Prevalence of Low Nephron Number at Birth: Risk Factor for CKD.

Kidney360, 1(8):863-879.

There is greater than tenfold variation in nephron number of the human kidney at birth. Although low nephron number is a recognized risk factor for CKD, its determinants are poorly understood. Evolutionary medicine represents a new discipline that seeks evolutionary explanations for disease, broadening perspectives on research and public health initiatives. Evolution of the kidney, an organ rich in mitochondria, has been driven by natural selection for reproductive fitness constrained by energy availability. Over the past 2 million years, rapid growth of an energy-demanding brain in Homo sapiens enabled hominid adaptation to environmental extremes through selection for mutations in mitochondrial and nuclear DNA epigenetically regulated by allocation of energy to developing organs. Maternal undernutrition or hypoxia results in intrauterine growth restriction or preterm birth, resulting in low birth weight and low nephron number. Regulated through placental transfer, environmental oxygen and nutrients signal nephron progenitor cells to reprogram metabolism from glycolysis to oxidative phosphorylation. These processes are modulated by counterbalancing anabolic and catabolic metabolic pathways that evolved from prokaryote homologs and by hypoxia-driven and autophagy pathways that evolved in eukaryotes. Regulation of nephron differentiation by histone modifications and DNA methyltransferases provide epigenetic control of nephron number in response to energy available to the fetus. Developmental plasticity of nephrogenesis represents an evolved life history strategy that prioritizes energy to early brain growth with adequate kidney function through reproductive years, the trade-off being increasing prevalence of CKD delayed until later adulthood. The research implications of this evolutionary analysis are to identify regulatory pathways of energy allocation directing nephrogenesis while accounting for the different life history strategies of animal models such as the mouse. The clinical implications are to optimize nutrition and minimize hypoxic/toxic stressors in childbearing women and children in early postnatal development.

RevDate: 2020-09-28

Noiret A, Puch L, Riffaud C, et al (2020)

Sex-Specific Response to Caloric Restriction After Reproductive Investment in Microcebus murinus: An Integrative Approach.

Frontiers in physiology, 11:506.

In seasonal environments, males and females usually maintain high metabolic activity during the whole summer season, exhausting their energy reserves. In the global warming context, unpredictability of food availability during summer could dramatically challenge the energy budget of individuals. Therefore, one can predict that resilience to environmental stress would be dramatically endangered during summer. Here, we hypothesized that females could have greater capacity to survive harsh conditions than males, considering the temporal shift in their respective reproductive energy investment, which can challenge them differently, as well as enhanced flexibility in females' physiological regulation. We tackled this question on the gray mouse lemur (Microcebus murinus), focusing on the late summer period, after the reproductive effort. We monitored six males and six females before and after a 2-weeks 60% caloric restriction (CR), measuring different physiological and cellular parameters in an integrative and comparative multiscale approach. Before CR, females were heavier than males and mostly characterized by high levels of energy expenditure, a more energetic mitochondrial profile and a downregulation of blood antioxidants. We observed a similar energy balance between sexes due to CR, with a decrease in metabolic activity over time only in males. Oxidative damage to DNA was also reduced by different pathways between sexes, which may reflect variability in their physiological status and life-history traits at the end of summer. Finally, females' mitochondria seemed to exhibit greater flexibility and greater metabolic potential than males in response to CR. Our results showed strong differences between males and females in response to food shortage during late summer, underlining the necessity to consider sex as a factor for population dynamics in climate change models.

RevDate: 2021-03-29
CmpDate: 2021-03-29

Vertika S, Singh KK, S Rajender (2020)

Mitochondria, spermatogenesis, and male infertility - An update.

Mitochondrion, 54:26-40.

The incorporation of mitochondria in the eukaryotic cell is one of the most enigmatic events in the course of evolution. This important organelle was thought to be only the powerhouse of the cell, but was later learnt to perform many other indispensable functions in the cell. Two major contributions of mitochondria in spermatogenesis concern energy production and apoptosis. Apart from this, mitochondria also participate in a number of other processes affecting spermatogenesis and fertility. Mitochondria in sperm are arranged in the periphery of the tail microtubules to serve to energy demand for motility. Apart from this, the role of mitochondria in germ cell proliferation, mitotic regulation, and the elimination of germ cells by apoptosis are now well recognized. Eventually, mutations in the mitochondrial genome have been reported in male infertility, particularly in sluggish sperm (asthenozoospermia); however, heteroplasmy in the mtDNA and a complex interplay between the nucleus and mitochondria affect their penetrance. In this article, we have provided an update on the role of mitochondria in various events of spermatogenesis and male fertility and on the correlation of mitochondrial DNA mutations with male infertility.

RevDate: 2020-10-19
CmpDate: 2020-10-19

Seebacher F (2020)

Is Endothermy an Evolutionary By-Product?.

Trends in ecology & evolution, 35(6):503-511.

Endothermy alters the energetic relationships between organisms and their environment and thereby influences fundamental niches. Endothermy is closely tied to energy metabolism. Regulation of energy balance is indispensable for all life and regulatory pathways increase in complexity from bacteria to vertebrates. Increasing complexity of metabolic networks also increase the probability for endothermic phenotypes to appear. Adaptive arguments are problematic epistemologically because the regulatory mechanisms enabling endothermy have not evolved for the 'purpose' of endothermy and the utility of current traits is likely to have changed over evolutionary time. It is most parsimonious to view endothermy as the evolutionary by-product of energy balance regulation rather than as an adaptation and interpret its evolution in the context of metabolic networks.

RevDate: 2021-03-29
CmpDate: 2021-03-29

Meduri GU, GP Chrousos (2020)

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections.

Frontiers in endocrinology, 11:161.

In critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (GRα) and are associated with an enormous bioenergetic and metabolic cost. Appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. Emerging literature place the activated GRα at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. By the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. We review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. Importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. Since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing GRα and mitochondria number and function. Present understanding of the activated GC-GRα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. The activated GRα interdependence with functional mitochondria and three vitamin reserves (B1, C, and D) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis.

RevDate: 2021-04-27
CmpDate: 2021-04-27

Gangloff EJ, Schwartz TS, Klabacka R, et al (2020)

Mitochondria as central characters in a complex narrative: Linking genomics, energetics, pace-of-life, and aging in natural populations of garter snakes.

Experimental gerontology, 137:110967.

As a pacesetter for physiological processes, variation in metabolic rate can determine the shape of energetic trade-offs and thereby drive variation in life-history traits. In turn, such variation in metabolic performance and life-histories can have profound consequences for lifespan and lifetime fitness. Thus, the extent to which metabolic rate variation is due to phenotypic plasticity or fixed genetic differences among individuals or populations is likely to be shaped by natural selection. Here, we first present a generalized framework describing the central role of mitochondria in processes linking environmental, genomic, physiological, and aging variation. We then present a test of these relationships in an exemplary system: populations of garter snakes (Thamnophis elegans) exhibiting contrasting life-history strategies - fast-growing, early-reproducing, and fast-aging (FA) versus slow-growing, late-reproducing, and slow-aging (SA). Previous work has characterized divergences in mitochondrial function, reactive oxygen species processing, and whole-organism metabolic rate between these contrasting life-history ecotypes. Here, we report new data on cellular respiration and mitochondrial genomics and synthesize these results with previous work. We test hypotheses about the causes and implications of mitochondrial genome variation within this generalized framework. First, we demonstrate that snakes of the FA ecotype increase cellular metabolic rate across their lifespan, while the opposite pattern holds for SA snakes, implying that reduced energetic throughput is associated with a longer life. Second, we show that variants in mitochondrial genomes are segregating across the landscape in a manner suggesting selection on the physiological consequences of this variation in habitats varying in temperature, food availability, and rates of predation. Third, we demonstrate functional variation in whole-organism metabolic rate related to these mitochondrial genome sequence variants. With this synthesis of numerous datasets, we are able to further characterize how variation across levels of biological organization interact within this generalized framework and how this has resulted in the emergence of distinct life-history ecotypes that vary in their rates of aging and lifespan.

RevDate: 2020-09-28

Scorziello A, Borzacchiello D, Sisalli MJ, et al (2020)

Mitochondrial Homeostasis and Signaling in Parkinson's Disease.

Frontiers in aging neuroscience, 12:100.

The loss of dopaminergic (DA) neurons in the substantia nigra leads to a progressive, long-term decline of movement and other non-motor deficits. The symptoms of Parkinson's disease (PD) often appear later in the course of the disease, when most of the functional dopaminergic neurons have been lost. The late onset of the disease, the severity of the illness, and its impact on the global health system demand earlier diagnosis and better targeted therapy. PD etiology and pathogenesis are largely unknown. There are mutations in genes that have been linked to PD and, from these complex phenotypes, mitochondrial dysfunction emerged as central in the pathogenesis and evolution of PD. In fact, several PD-associated genes negatively impact on mitochondria physiology, supporting the notion that dysregulation of mitochondrial signaling and homeostasis is pathogenically relevant. Derangement of mitochondrial homeostatic controls can lead to oxidative stress and neuronal cell death. Restoring deranged signaling cascades to and from mitochondria in PD neurons may then represent a viable opportunity to reset energy metabolism and delay the death of dopaminergic neurons. Here, we will highlight the relevance of dysfunctional mitochondrial homeostasis and signaling in PD, the molecular mechanisms involved, and potential therapeutic approaches to restore mitochondrial activities in damaged neurons.

RevDate: 2021-06-18
CmpDate: 2021-06-18

Aparicio-Trejo OE, Avila-Rojas SH, Tapia E, et al (2020)

Chronic impairment of mitochondrial bioenergetics and β-oxidation promotes experimental AKI-to-CKD transition induced by folic acid.

Free radical biology & medicine, 154:18-32.

Recent studies suggest that mitochondrial bioenergetics and oxidative stress alterations may be common mechanisms involved in the progression of renal damage. However, the evolution of the mitochondrial alterations over time and the possible effects that their prevention could have in the progression of renal damage are not clear. Folic acid (FA)-induced kidney damage is a widely used experimental model to induce acute kidney injury (AKI), which can evolve to chronic kidney disease (CKD). Therefore, it has been extensively applied to study the mechanisms involved in AKI-to-CKD transition. We previously demonstrated that one day after FA administration, N-acetyl-cysteine (NAC) pre-administration prevented the development of AKI induced by FA. Such therapeutic effect was related to mitochondrial preservation. In the present study, we characterized the temporal course of mitochondrial bioenergetics and redox state alterations along the progression of renal damage induced by FA. Mitochondrial function was studied at different time points and showed a sustained impairment in oxidative phosphorylation capacity and a decrease in β-oxidation, decoupling, mitochondrial membrane potential depolarization and a pro-oxidative state, attributed to the reduction in activity of complexes I and III and mitochondrial cristae effacement, thus favoring the transition from AKI to CKD. Furthermore, the mitochondrial protection by NAC administration before AKI prevented not only the long-term deterioration of mitochondrial function at the chronic stage, but also CKD development. Taken together, our results support the idea that the prevention of mitochondrial dysfunction during an AKI event can be a useful strategy to prevent the transition to CKD.

RevDate: 2021-08-10
CmpDate: 2021-08-10

Rotterová J, Salomaki E, Pánek T, et al (2020)

Genomics of New Ciliate Lineages Provides Insight into the Evolution of Obligate Anaerobiosis.

Current biology : CB, 30(11):2037-2050.e6.

Oxygen plays a crucial role in energetic metabolism of most eukaryotes. Yet adaptations to low-oxygen concentrations leading to anaerobiosis have independently arisen in many eukaryotic lineages, resulting in a broad spectrum of reduced and modified mitochondrion-related organelles (MROs). In this study, we present the discovery of two new class-level lineages of free-living marine anaerobic ciliates, Muranotrichea, cl. nov. and Parablepharismea, cl. nov., that, together with the class Armophorea, form a major clade of obligate anaerobes (APM ciliates) within the Spirotrichea, Armophorea, and Litostomatea (SAL) group. To deepen our understanding of the evolution of anaerobiosis in ciliates, we predicted the mitochondrial metabolism of cultured representatives from all three classes in the APM clade by using transcriptomic and metagenomic data and performed phylogenomic analyses to assess their evolutionary relationships. The predicted mitochondrial metabolism of representatives from the APM ciliates reveals functional adaptations of metabolic pathways that were present in their last common ancestor and likely led to the successful colonization and diversification of the group in various anoxic environments. Furthermore, we discuss the possible relationship of Parablepharismea to the uncultured deep-sea class Cariacotrichea on the basis of single-gene analyses. Like most anaerobic ciliates, all studied species of the APM clade host symbionts, which we propose to be a significant accelerating factor in the transitions to an obligately anaerobic lifestyle. Our results provide an insight into the evolutionary mechanisms of early transitions to anaerobiosis and shed light on fine-scale adaptations in MROs over a relatively short evolutionary time frame.

RevDate: 2021-08-23
CmpDate: 2021-08-23

Rodríguez M, Valez V, Cimarra C, et al (2020)

Hypoxic-Ischemic Encephalopathy and Mitochondrial Dysfunction: Facts, Unknowns, and Challenges.

Antioxidants & redox signaling, 33(4):247-262.

Significance: Hypoxic-ischemic events due to intrapartum complications represent the second cause of neonatal mortality and initiate an acute brain disorder known as hypoxic-ischemic encephalopathy (HIE). In HIE, the brain undergoes primary and secondary energy failure phases separated by a latent phase in which partial neuronal recovery is observed. A hypoxic-ischemic event leads to oxygen restriction causing ATP depletion, neuronal oxidative stress, and cell death. Mitochondrial dysfunction and enhanced oxidant formation in brain cells are characteristic phenomena associated with energy failure. Recent Advances: Mitochondrial sources of oxidants in neurons include complex I of the mitochondrial respiratory chain, as a key contributor to O2[•-] production via succinate by a reverse electron transport mechanism. The reaction of O2[•-] with nitric oxide ([•]NO) yields peroxynitrite, a mitochondrial and cellular toxin. Quantitation of the redox state of cytochrome c oxidase, through broadband near-infrared spectroscopy, represents a promising monitoring approach to evaluate mitochondrial dysfunction in vivo in humans, in conjunction with the determination of cerebral oxygenation and their correlation with the severity of brain injury. Critical Issues: The energetic failure being a key phenomenon in HIE connected with the severity of the encephalopathy, measurement of mitochondrial dysfunction in vivo provides an approach to assess evolution, prognosis, and adequate therapies. Restoration of mitochondrial redox homeostasis constitutes a key therapeutic goal. Future Directions: While hypothermia is the only currently accepted therapy in clinical management to preserve mitochondrial function, other mitochondria-targeted and/or redox-based treatments are likely to synergize to ensure further efficacy.

RevDate: 2021-08-06
CmpDate: 2021-08-06

de Brito Monteiro L, Davanzo GG, de Aguiar CF, et al (2020)

M-CSF- and L929-derived macrophages present distinct metabolic profiles with similar inflammatory outcomes.

Immunobiology, 225(3):151935.

Macrophages are essential components of the immune system. Macrophages can be derived from the bone marrow of mice with either recombinant M-CSF or L929 supernatant. Recent literature considers recombinant M-CSF- and L929-derived macrophages as equals, even though L929-derived macrophages are exposed to other substances secreted in the L929 supernatant, and not only M-CSF. Thus, we decided to perform a comparative analysis of both inflammatory and metabolic profiles of macrophages differentiated under the aforementioned conditions, which is relevant for standardization and interpretation of in vitro studies. We observed that, when treated with LPS, L929macs secrete lower levels of proinflammatory cytokines (TNF-α, IL-6, IL12) and present higher glycolysis and oxygen consumption when compared with M-CSFmacs. L929macs also have increased mitochondrial mass, with higher percentage of dysfunctional mitochondria. This sort of information can help direct further studies towards a more specific approach for macrophage generation.

RevDate: 2020-11-19
CmpDate: 2020-11-19

Lang SA, McIlroy P, DH Shain (2020)

Structural Evolution of the Glacier Ice Worm Fo ATP Synthase Complex.

The protein journal, 39(2):152-159.

The segmented annelid worm, Mesenchytraeus solifugus, is a permanent resident of temperate, maritime glaciers in the Pacific northwestern region of North America, displaying atypically high intracellular ATP levels which have been linked to its unusual ability to thrive in hydrated glacier ice. We have shown previously that ice worms contain a highly basic, carboxy terminal extension on their ATP6 regulatory subunit, likely acquired by horizontal gene transfer from a microbial dietary source. Here we examine the full complement of F1F0 ATP synthase structural subunits with attention to non-conservative, ice worm-specific structural modifications. Our genomics analyses and molecular models identify putative proton shuttling domains on either side of the F0 hemichannel, which predictably function to enhance proton flow across the mitochondrial membrane. Other components of the ice worm ATP synthase complex have remained largely unchanged in the context of Metazoan evolution.

RevDate: 2021-04-01
CmpDate: 2021-04-01

Boël M, Romestaing C, Duchamp C, et al (2020)

Improved mitochondrial coupling as a response to high mass-specific metabolic rate in extremely small mammals.

The Journal of experimental biology, 223(Pt 5): pii:jeb.215558.

Mass-specific metabolic rate negatively co-varies with body mass from the whole-animal to the mitochondrial levels. Mitochondria are the mainly consumers of oxygen inspired by mammals to generate ATP or compensate for energetic losses dissipated as the form of heat (proton leak) during oxidative phosphorylation. Consequently, ATP synthesis and proton leak compete for the same electrochemical gradient. Because proton leak co-varies negatively with body mass, it is unknown whether extremely small mammals further decouple their mitochondria to maintain their body temperature or whether they implement metabolic innovations to ensure cellular homeostasis. The present study investigated the impact of body mass variation on cellular and mitochondrial functioning in small mammals, comparing two extremely small African pygmy mice (Mus mattheyi, ∼5 g, and Mus minutoides, ∼7 g) with the larger house mouse (Mus musculus, ∼22 g). Oxygen consumption rates were measured from the animal to the mitochondrial levels. We also measured mitochondrial ATP synthesis in order to appreciate the mitochondrial efficiency (ATP/O). At the whole-animal scale, mass- and surface-specific metabolic rates co-varied negatively with body mass, whereas this was not necessarily the case at the cellular and mitochondrial levels. Mus mattheyi had generally the lowest cellular and mitochondrial fluxes, depending on the tissue considered (liver or skeletal muscle), as well as having more-efficient muscle mitochondria than the other two species. Mus mattheyi presents metabolic innovations to ensure its homeostasis, by generating more ATP per oxygen consumed.

RevDate: 2021-02-23
CmpDate: 2021-02-23

Muthye V, Kandoi G, DV Lavrov (2020)

MMPdb and MitoPredictor: Tools for facilitating comparative analysis of animal mitochondrial proteomes.

Mitochondrion, 51:118-125.

Data on experimentally-characterized animal mitochondrial proteomes (mt-proteomes) are limited to a few model organisms and are scattered across multiple databases, impeding a comparative analysis. We developed two resources to address these problems. First, we re-analyzed proteomic data from six species with experimentally characterized mt-proteomes: animals (Homo sapiens, Mus musculus, Caenorhabditis elegans, and Drosophila melanogaster), and outgroups (Acanthamoeba castellanii and Saccharomyces cerevisiae) and created the Metazoan Mitochondrial Proteome Database (MMPdb) to host the results. Second, we developed a novel pipeline, "MitoPredictor" that uses a Random Forest classifier to infer mitochondrial localization of proteins based on orthology, mitochondrial targeting signal prediction, and protein domain analyses. Both tools generate an R Shiny applet that can be used to visualize and interact with the results and can be used on a personal computer. MMPdb is also available online at

RevDate: 2020-09-08
CmpDate: 2020-09-08

Chevigny N, Schatz-Daas D, Lotfi F, et al (2020)

DNA Repair and the Stability of the Plant Mitochondrial Genome.

International journal of molecular sciences, 21(1):.

The mitochondrion stands at the center of cell energy metabolism. It contains its own genome, the mtDNA, that is a relic of its prokaryotic symbiotic ancestor. In plants, the mitochondrial genetic information influences important agronomic traits including fertility, plant vigor, chloroplast function, and cross-compatibility. Plant mtDNA has remarkable characteristics: It is much larger than the mtDNA of other eukaryotes and evolves very rapidly in structure. This is because of recombination activities that generate alternative mtDNA configurations, an important reservoir of genetic diversity that promotes rapid mtDNA evolution. On the other hand, the high incidence of ectopic recombination leads to mtDNA instability and the expression of gene chimeras, with potential deleterious effects. In contrast to the structural plasticity of the genome, in most plant species the mtDNA coding sequences evolve very slowly, even if the organization of the genome is highly variable. Repair mechanisms are probably responsible for such low mutation rates, in particular repair by homologous recombination. Herein we review some of the characteristics of plant organellar genomes and of the repair pathways found in plant mitochondria. We further discuss how homologous recombination is involved in the evolution of the plant mtDNA.

RevDate: 2021-05-18

Mélanie B, Caroline R, Claude D, et al (2020)

Improved mitochondrial coupling as a response to high mass-specific metabolic rate in extremely small mammals.

The Journal of experimental biology pii:267493 [Epub ahead of print].

Mass-specific metabolic rate negatively co-varies with body mass from the whole-animal to the mitochondrial levels. Mitochondria are the mainly consumers of oxygen inspired by mammals to generate ATP or compensate energetic losses dissipated as the form of heat (proton leak) during oxidative phosphorylation. Consequently, ATP synthesis and proton leak thus compete for the same electrochemical gradient. Because proton leak co-varies negatively with body mass, it is unknown if extremely small mammals further decouple their mitochondria to maintain their body temperature or if they implement metabolic innovations to ensure cellular homeostasis. The present study investigates the impact of body mass variation on cellular and mitochondrial functioning in small mammals, comparing the two extremely small African pygmy mice (Mus mattheyi, approx. 5 g and Mus minutoides, approx. 7 g) with the larger house mouse (Mus musculus, approx. 22 g). Oxygen consumption rates were measured from the animal to the mitochondrial levels. We also measured mitochondrial ATP synthesis in order to appreciate the mitochondrial efficiency (ATP/O). At the whole-animal scale, mass- and surface-specific metabolic rates co-varied negatively with body mass, whereas this was not necessarily the case at cellular and mitochondrial levels. M. mattheyi had generally the lowest cellular and mitochondrial fluxes, depending on the tissue considered (liver or skeletal muscle), as well as having higher efficient muscle mitochondria than the other two species. M. mattheyi presents metabolic innovations to ensure its homeostasis, by generating more ATP per oxygen consumed.

RevDate: 2022-12-07
CmpDate: 2020-03-12

Liu Y, Qu J, Zhang L, et al (2019)

Identification and characterization of the TCA cycle genes in maize.

BMC plant biology, 19(1):592.

BACKGROUND: The tricarboxylic acid (TCA) cycle is crucial for cellular energy metabolism and carbon skeleton supply. However, the detailed functions of the maize TCA cycle genes remain unclear.

RESULTS: In this study, 91 TCA genes were identified in maize by a homology search, and they were distributed on 10 chromosomes and 1 contig. Phylogenetic results showed that almost all maize TCA genes could be classified into eight major clades according to their enzyme families. Sequence alignment revealed that several genes in the same subunit shared high protein sequence similarity. The results of cis-acting element analysis suggested that several TCA genes might be involved in signal transduction and plant growth. Expression profile analysis showed that many maize TCA cycle genes were expressed in specific tissues, and replicate genes always shared similar expression patterns. Moreover, qPCR analysis revealed that some TCA genes were highly expressed in the anthers at the microspore meiosis phase. In addition, we predicted the potential interaction networks among the maize TCA genes. Next, we cloned five TCA genes located on different TCA enzyme complexes, Zm00001d008244 (isocitrate dehydrogenase, IDH), Zm00001d017258 (succinyl-CoA synthetase, SCoAL), Zm00001d025258 (α-ketoglutarate dehydrogenase, αKGDH), Zm00001d027558 (aconitase, ACO) and Zm00001d044042 (malate dehydrogenase, MDH). Confocal observation showed that their protein products were mainly localized to the mitochondria; however, Zm00001d025258 and Zm00001d027558 were also distributed in the nucleus, and Zm00001d017258 and Zm00001d044042 were also located in other unknown positions in the cytoplasm. Through the bimolecular fluorescent complimentary (BiFC) method, it was determined that Zm00001d027558 and Zm00001d044042 could form homologous dimers, and both homologous dimers were mainly distributed in the mitochondria. However, no heterodimers were detected between these five genes. Finally, Arabidopsis lines overexpressing the above five genes were constructed, and those transgenic lines exhibited altered primary root length, salt tolerance, and fertility.

CONCLUSION: Sequence compositions, duplication patterns, phylogenetic relationships, cis-elements, expression patterns, and interaction networks were investigated for all maize TCA cycle genes. Five maize TCA genes were overexpressed in Arabidopsis, and they could alter primary root length, salt tolerance, and fertility. In conclusion, our findings may help to reveal the molecular function of the TCA genes in maize.

RevDate: 2021-01-10
CmpDate: 2020-11-09

Terrien J, Seugnet I, Seffou B, et al (2019)

Reduced central and peripheral inflammatory responses and increased mitochondrial activity contribute to diet-induced obesity resistance in WSB/EiJ mice.

Scientific reports, 9(1):19696.

Energy imbalance due to excess of calories is considered to be a major player in the current worldwide obesity pandemic and could be accompanied by systemic and central inflammation and mitochondrial dysfunctions. This hypothesis was tested by comparing the wild-derived diet-induced obesity- (DIO-) resistant mouse strain WSB/EiJ to the obesity-prone C57BL/6J strain. We analysed circulating and hypothalamic markers of inflammatory status and hypothalamic mitochondrial activity in both strains exposed to high-fat diet (HFD). We further analysed the regulations of hypothalamic genes involved in inflammation and mitochondrial pathways by high throughput microfluidic qPCR on RNA extracted from laser micro-dissected arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei. HFD induced increased body weight gain, circulating levels of leptin, cholesterol, HDL and LDL in C57BL/6J whereas WSB/EiJ mice displayed a lower inflammatory status, both peripherally (lower levels of circulating cytokines) and centrally (less activated microglia in the hypothalamus) as well as more reactive mitochondria in the hypothalamus. The gene expression data analysis allowed identifying strain-specific hypothalamic metabolic pathways involved in the respective responses to HFD. Our results point to the involvement of hypothalamic inflammatory and mitochondrial pathways as key factors in the control of energy homeostasis and the resistance to DIO.

RevDate: 2020-04-20
CmpDate: 2020-04-20

Arnedo M, Latorre-Pellicer A, Lucia-Campos C, et al (2019)

More Than One HMG-CoA Lyase: The Classical Mitochondrial Enzyme Plus the Peroxisomal and the Cytosolic Ones.

International journal of molecular sciences, 20(24):.

There are three human enzymes with HMG-CoA lyase activity that are able to synthesize ketone bodies in different subcellular compartments. The mitochondrial HMG-CoA lyase was the first to be described, and catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA to acetoacetate and acetyl-CoA, the common final step in ketogenesis and leucine catabolism. This protein is mainly expressed in the liver and its function is metabolic, since it produces ketone bodies as energetic fuels when glucose levels are low. Another isoform is encoded by the same gene for the mitochondrial HMG-CoA lyase (HMGCL), but it is located in peroxisomes. The last HMG-CoA lyase to be described is encoded by a different gene, HMGCLL1, and is located in the cytosolic side of the endoplasmic reticulum membrane. Some activity assays and tissue distribution of this enzyme have shown the brain and lung as key tissues for studying its function. Although the roles of the peroxisomal and cytosolic HMG-CoA lyases remain unknown, recent studies highlight the role of ketone bodies in metabolic remodeling, homeostasis, and signaling, providing new insights into the molecular and cellular function of these enzymes.

RevDate: 2021-01-20
CmpDate: 2020-11-17

Elbassiouny AA, Lovejoy NR, BSW Chang (2020)

Convergent patterns of evolution of mitochondrial oxidative phosphorylation (OXPHOS) genes in electric fishes.

Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 375(1790):20190179.

The ability to generate and detect electric fields has evolved in several groups of fishes as a means of communication, navigation and, occasionally, predation. The energetic burden required can account for up to 20% of electric fishes' daily energy expenditure. Despite this, molecular adaptations that enable electric fishes to meet the metabolic demands of bioelectrogenesis remain unknown. Here, we investigate the molecular evolution of the mitochondrial oxidative phosphorylation (OXPHOS) complexes in the two most diverse clades of weakly electric fishes-South American Gymnotiformes and African Mormyroidea, using codon-based likelihood approaches. Our analyses reveal that although mitochondrial OXPHOS genes are generally subject to strong purifying selection, this constraint is significantly reduced in electric compared to non-electric fishes, particularly for complexes IV and V. Moreover, analyses of concatenated mitochondrial genes show strong evidence for positive selection in complex I genes on the two branches associated with the independent evolutionary origins of electrogenesis. These results suggest that adaptive evolution of proton translocation in the OXPHOS cellular machinery may be associated with the evolution of bioelectrogenesis. Overall, we find striking evidence for remarkably similar effects of electrogenesis on the molecular evolution of mitochondrial OXPHOS genes in two independently derived clades of electrogenic fishes. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.

RevDate: 2021-01-20
CmpDate: 2020-11-17

Bettinazzi S, Nadarajah S, Dalpé A, et al (2020)

Linking paternally inherited mtDNA variants and sperm performance.

Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 375(1790):20190177.

Providing robust links between mitochondrial genotype and phenotype is of major importance given that mitochondrial DNA (mtDNA) variants can affect reproductive success. Because of the strict maternal inheritance (SMI) of mitochondria in animals, haplotypes that negatively affect male fertility can become fixed in populations. This phenomenon is known as 'mother's curse'. Doubly uniparental inheritance (DUI) of mitochondria is a stable exception in bivalves, which entails two mtDNA lineages that evolve independently and are transmitted separately through oocytes and sperm. This makes the DUI mitochondrial lineages subject to different sex-specific selective sieves during mtDNA evolution, thus DUI is a unique model to evaluate how direct selection on sperm mitochondria could contribute to male reproductive fitness. In this study, we tested the impact of mtDNA variants on sperm performance and bioenergetics in DUI and SMI species. Analyses also involved measures of sperm performance following inhibition of main energy pathways and sperm response to oocyte presence. Compared to SMI, DUI sperm exhibited (i) low speed and linearity, (ii) a strict OXPHOS-dependent strategy of energy production, and (iii) a partial metabolic shift towards fermentation following egg detection. Discussion embraces the adaptive value of mtDNA variation and suggests a link between male-energetic adaptation, fertilization success and paternal mitochondria preservation. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.

RevDate: 2021-01-20
CmpDate: 2020-11-17

Camus MF, O'Leary M, Reuter M, et al (2020)

Impact of mitonuclear interactions on life-history responses to diet.

Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 375(1790):20190416.

Mitochondria are central to both energy metabolism and biosynthesis. Mitochondrial function could therefore influence resource allocation. Critically, mitochondrial function depends on interactions between proteins encoded by the mitochondrial and nuclear genomes. Severe incompatibilities between these genomes can have pervasive effects on both fitness and longevity. How milder deficits in mitochondrial function affect life-history trade-offs is less well understood. Here, we analyse how mitonuclear interactions affect the trade-off between fecundity and longevity in Drosophila melanogaster. We consider a panel of 10 different mitochondrial DNA haplotypes against two contrasting nuclear backgrounds (w[1118] (WE) and Zim53 (ZIM)) in response to high-protein versus standard diet. We report strikingly different responses between the two nuclear backgrounds. WE females have higher fecundity and decreased longevity on high protein. ZIM females have much greater fecundity and shorter lifespan than WE flies on standard diet. High protein doubled their fecundity with no effect on longevity. Mitochondrial haplotype reflected nuclear life-history trade-offs, with a negative correlation between longevity and fecundity in WE flies and no correlation in ZIM flies. Mitonuclear interactions had substantial effects but did not reflect genetic distance between mitochondrial haplotypes. We conclude that mitonuclear interactions can have significant impact on life-history trade-offs, but their effects are not predictable by relatedness. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.

RevDate: 2020-12-14
CmpDate: 2020-12-10

Shen Y, Wang X, Guo S, et al (2020)

Evolutionary genomics analysis of human nucleus-encoded mitochondrial genes: implications for the roles of energy production and metabolic pathways in the pathogenesis and pathophysiology of demyelinating diseases.

Neuroscience letters, 715:134600.

The myelin sheath is a plasma membrane extension that lines nerve fibers to protect, support and insulate neurons. The myelination of axons in vertebrates enables fast, saltatory impulse propagation, and this process relies on organelles, especially on mitochondria to supply energy. Approximately 99% of mitochondrial proteins are encoded in the nucleus. Since mitochondria play a central role in the energy production and metabolic pathways, which are essential for myelinogenesis, studying these nucleus-encoded genes (nMGs) may provide new insights into the roles of energy metabolism in demyelinating diseases. In this work, a multiomics-based approach was employed to 1) construct a 1,740 human nMG subset with mitochondrial localization evidence obtained from the Integrated Mitochondrial Protein Index (IMPI) and MitoCarta databases, 2) conduct an evolutionary genomics analysis across mouse, rat, monkey, chimp, and human models, 3) examine dysmyelination phenotype-related genes (nMG subset genes with oligodendrocyte- and myelin-related phenotypes, OMP-nMGs) in MGI mouse lines and human patients, 4) determine the expression discrepancy of OMP-nMGs in brain tissues of cuprizone-treated mice, multiple sclerosis patients, and normal controls, and 5) conduct literature data mining to explore OMP-nMG-associated disease impacts. By contrasting OMP-nMGs with other genes, OMP-nMGs were found to be more ubiquitously expressed (59.1% vs. 16.1%), disease-associated (67.3% vs. 20.2%), and evolutionarily conserved within the human populations. Our multiomics-based analysis identified 110 OMP-nMGs implicated in energy production and lipid and glycan biosynthesis in the pathogenesis and pathophysiology of demyelinating disorders. Future targeted characterization of OMP-nMGs in abnormal myelination conditions may allow the discovery of novel nMG mediated mechanisms underlying myelinogenesis and related diseases.

RevDate: 2020-03-26
CmpDate: 2020-03-26

Poljsak B, Kovac V, Dahmane R, et al (2019)

Cancer Etiology: A Metabolic Disease Originating from Life's Major Evolutionary Transition?.

Oxidative medicine and cellular longevity, 2019:7831952.

A clear understanding of the origins of cancer is the basis of successful strategies for effective cancer prevention and management. The origin of cancer at the molecular and cellular levels is not well understood. Is the primary cause of the origin of cancer the genomic instability or impaired energy metabolism? An attempt was made to present cancer etiology originating from life's major evolutionary transition. The first evolutionary transition went from simple to complex cells when eukaryotic cells with glycolytic energy production merged with the oxidative mitochondrion (The Endosymbiosis Theory first proposed by Lynn Margulis in the 1960s). The second transition went from single-celled to multicellular organisms once the cells obtained mitochondria, which enabled them to obtain a higher amount of energy. Evidence will be presented that these two transitions, as well as the decline of NAD+ and ATP levels, are the root of cancer diseases. Restoring redox homeostasis and reactivation of mitochondrial oxidative metabolism are important factors in cancer prevention.

RevDate: 2021-02-12
CmpDate: 2020-09-28

Johnson RJ, Stenvinkel P, Andrews P, et al (2020)

Fructose metabolism as a common evolutionary pathway of survival associated with climate change, food shortage and droughts.

Journal of internal medicine, 287(3):252-262.

Mass extinctions occur frequently in natural history. While studies of animals that became extinct can be informative, it is the survivors that provide clues for mechanisms of adaptation when conditions are adverse. Here, we describe a survival pathway used by many species as a means for providing adequate fuel and water, while also providing protection from a decrease in oxygen availability. Fructose, whether supplied in the diet (primarily fruits and honey), or endogenously (via activation of the polyol pathway), preferentially shifts the organism towards the storing of fuel (fat, glycogen) that can be used to provide energy and water at a later date. Fructose causes sodium retention and raises blood pressure and likely helped survival in the setting of dehydration or salt deprivation. By shifting energy production from the mitochondria to glycolysis, fructose reduced oxygen demands to aid survival in situations where oxygen availability is low. The actions of fructose are driven in part by vasopressin and the generation of uric acid. Twice in history, mutations occurred during periods of mass extinction that enhanced the activity of fructose to generate fat, with the first being a mutation in vitamin C metabolism during the Cretaceous-Paleogene extinction (65 million years ago) and the second being a mutation in uricase that occurred during the Middle Miocene disruption (12-14 million years ago). Today, the excessive intake of fructose due to the availability of refined sugar and high-fructose corn syrup is driving 'burden of life style' diseases, including obesity, diabetes and high blood pressure.

RevDate: 2021-01-10
CmpDate: 2020-01-13

Smith SR, Dupont CL, McCarthy JK, et al (2019)

Evolution and regulation of nitrogen flux through compartmentalized metabolic networks in a marine diatom.

Nature communications, 10(1):4552.

Diatoms outcompete other phytoplankton for nitrate, yet little is known about the mechanisms underpinning this ability. Genomes and genome-enabled studies have shown that diatoms possess unique features of nitrogen metabolism however, the implications for nutrient utilization and growth are poorly understood. Using a combination of transcriptomics, proteomics, metabolomics, fluxomics, and flux balance analysis to examine short-term shifts in nitrogen utilization in the model pennate diatom in Phaeodactylum tricornutum, we obtained a systems-level understanding of assimilation and intracellular distribution of nitrogen. Chloroplasts and mitochondria are energetically integrated at the critical intersection of carbon and nitrogen metabolism in diatoms. Pathways involved in this integration are organelle-localized GS-GOGAT cycles, aspartate and alanine systems for amino moiety exchange, and a split-organelle arginine biosynthesis pathway that clarifies the role of the diatom urea cycle. This unique configuration allows diatoms to efficiently adjust to changing nitrogen status, conferring an ecological advantage over other phytoplankton taxa.

RevDate: 2021-04-21
CmpDate: 2020-05-25

Guièze R, Liu VM, Rosebrock D, et al (2019)

Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies.

Cancer cell, 36(4):369-384.e13.

Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.


ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

Electronic Scholarly Publishing
961 Red Tail Lane
Bellingham, WA 98226

E-mail: RJR8222 @

Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin and even a collection of poetry — Chicago Poems by Carl Sandburg.


ESP now offers a large collection of user-selected side-by-side timelines (e.g., all science vs. all other categories, or arts and culture vs. world history), designed to provide a comparative context for appreciating world events.


Biographical information about many key scientists (e.g., Walter Sutton).

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )