bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2024–12–29
twelve papers selected by
Jessica Rosarda, Uniformed Services University
  1. Impairment of lipid homeostasis causes lysosomal accumulation of endogenous protein aggregates through ESCRT disruption.
  2. Simultaneous Imaging of pH and Peroxynitrite in the Endoplasmic Reticulum and Mitochondria: Revealing Organelle Interactions in Alzheimer's Disease Pathogenesis.
  3. Trimethylamine-N-oxide accelerates osteoporosis by PERK activation of ATF5 unfolding.
  4. Non-enzymatic posttranslational protein modifications in protein aggregation and neurodegenerative diseases.
  5. The Mitochondrial Blueprint: Unlocking Secondary Metabolite Production.
  6. Formyl-methionine-mediated eukaryotic ribosome quality control pathway for cold adaptation.
  7. Acetylation-Mediated Post-Translational Modification of Pyruvate Dehydrogenase Plays a Critical Role in the Regulation of the Cellular Acetylome During Metabolic Stress.
  8. Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases.
  9. Phosphatidic acid as a cofactor of mTORC1 in platinum-based chemoresistance: Mechanisms and therapeutic potential.
  10. Essential role of sulfide oxidation in brain health and neurological disorders.
  11. Bacterial purine metabolism modulates C. elegans development and stress tolerance via DAF-16.
  12. Influence of the Microbial Metabolite Acetyl Phosphate on Mitochondrial Functions Under Conditions of Exogenous Acetylation and Alkalization.
  1. Elife. 2024 Dec 23. pii: RP86194. [Epub ahead of print]12
    Impairment of lipid homeostasis causes lysosomal accumulation of endogenous protein aggregates through ESCRT disruption.
    John Yong, Jacqueline E Villalta, Ngoc Vu, Matthew A Kukurugya, Niclas Olsson, Magdalena Preciado López, Julia R Lazzari-Dean, Kayley Hake, Fiona E McAllister, Bryson D Bennett, Calvin H Jan.
      Protein aggregation increases during aging and is a pathological hallmark of many age-related diseases. Protein homeostasis (proteostasis) depends on a core network of factors directly influencing protein production, folding, trafficking, and degradation. Cellular proteostasis also depends on the overall composition of the proteome and numerous environmental variables. Modulating this cellular proteostasis state can influence the stability of multiple endogenous proteins, yet the factors contributing to this state remain incompletely characterized. Here, we performed genome-wide CRISPRi screens to elucidate the modulators of proteostasis state in mammalian cells, using a fluorescent dye to monitor endogenous protein aggregation. These screens identified known components of the proteostasis network and uncovered a novel link between protein and lipid homeostasis. Increasing lipid uptake and/or disrupting lipid metabolism promotes the accumulation of sphingomyelins and cholesterol esters and drives the formation of detergent-insoluble protein aggregates at the lysosome. Proteome profiling of lysosomes revealed ESCRT accumulation, suggesting disruption of ESCRT disassembly, lysosomal membrane repair, and microautophagy. Lipid dysregulation leads to lysosomal membrane permeabilization but does not otherwise impact fundamental aspects of lysosomal and proteasomal functions. Together, these results demonstrate that lipid dysregulation disrupts ESCRT function and impairs proteostasis.
    Keywords:  CRISPR; ESCRT; aggregation; cell biology; human; lipid dysregulation; lysosome; proteostasis
    DOI:  https://doi.org/10.7554/eLife.86194
  2. Anal Chem. 2024 Dec 26.
    Simultaneous Imaging of pH and Peroxynitrite in the Endoplasmic Reticulum and Mitochondria: Revealing Organelle Interactions in Alzheimer's Disease Pathogenesis.
    Lushan Huang, Liyi Ma, Qiaowen Zhao, Qichen Zhu, Guangwei She, Lixuan Mu, Wensheng Shi.
      pH and peroxynitrite (ONOO-) are two critical biomarkers to unveil the corresponding status of endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which are closely related to Alzheimer's disease (AD). Simultaneously monitoring pH and ONOO- fluctuations in the ER and mitochondria during AD progression is pivotal for clarifying the interplay between the disorders of the two organelles and revealing AD pathogenesis. Herein, we designed and synthesized a dual-channel fluorescent probe (DCFP) to visualize pH and ONOO- in the ER and mitochondria. DCFP possessed excellent sensitivity and selectivity to pH and ONOO- without spectral crosstalk and was utilized in monitoring the two analytes within AD model cells and larval zebrafish. Importantly, DCFP could preferentially target mitochondria in normal cells and be enriched in the ER after mitochondrial depolarization. With the aid of DCFP, the slower acidification rate of the ER than that of mitochondria induced by Aβ oligomers (AβOs) was first identified, which could be ascribed to the relief of the AβOs-triggered ER stress through the Ca2+ migration from the ER to mitochondria. Moreover, continuous exposure to AβOs led to mitochondrial Ca2+ overload, accelerating the acidification and ONOO- overproduction within mitochondria. As a result, intracellular oxidative stress levels were elevated, further exacerbating ER stress and aggravating ER acidification in turn. The advanced understanding of the potential interplay between the ER and mitochondria in this work may offer new insights and methodologies for studying AD pathogenesis. The DCFP developed in this work could also be employed to study other diseases related to ER stress and mitochondrial dysfunction.
    DOI:  https://doi.org/10.1021/acs.analchem.4c03646
  3. Cell Mol Life Sci. 2024 Dec 24. 82(1): 13
    Trimethylamine-N-oxide accelerates osteoporosis by PERK activation of ATF5 unfolding.
    Yu-Han Lin, Wei-Shiung Lian, Re-Wen Wu, Yu-Shan Chen, Shin-Long Wu, Jih-Yang Ko, Shao-Yu Wang, Holger Jahr, Feng-Sheng Wang.
      Imbalances in gut microbiota and their metabolites have been implicated in osteoporotic disorders. Trimethylamine-n-oxide (TMAO), a metabolite of L-carnitine produced by gut microorganisms and flavin-containing monooxygenase-3, is known to accelerate tissue metabolism and remodeling; however, its role in bone loss remained unexplored. This study investigates the relationship between gut microbiota dysbiosis, TMAO production, and osteoporosis development. We further demonstrate that the loss of beneficial gut microbiota is associated with the development of murine osteoporosis and alterations in the serum metabolome, particularly affecting L-carnitine metabolism. TMAO emerges as a functional metabolite detrimental to bone homeostasis. Notably, transplantation of mouse gut microbiota counteracts obesity- or estrogen deficiency-induced TMAO overproduction and mitigates key features of osteoporosis. Mechanistically, excessive TMAO intake augments bone mass loss by inhibiting bone mineral acquisition and osteogenic differentiation. TMAO activates the PERK and ATF4-dependent disruption of endoplasmic reticulum autophagy and suppresses the folding of ATF5, hindering mitochondrial unfolding protein response (UPRmt) in osteoblasts. Importantly, UPRmt activation by nicotinamide riboside mitigates TMAO-induced inhibition of mineralized matrix biosynthesis by preserving mitochondrial oxidative phosphorylation and mitophagy. Collectively, our findings revealed that gut microbiota dysbiosis leads to TMAO overproduction, impairing ER homeostasis and UPRmt, thereby aggravating osteoblast dysfunction and development of osteoporosis. Our study elucidates the catabolic role of gut microflora-derived TMAO in bone integrity and highlights the therapeutic potential of healthy donor gut microbiota transplantation to alter the progression of osteoporosis.
    Keywords:  ER-phagy; Gut microecosystem; Misfolding; OXPHOS; Parkin; Trimethylamine-n-oxide
    DOI:  https://doi.org/10.1007/s00018-024-05501-y
  4. RSC Chem Biol. 2024 Dec 19.
    Non-enzymatic posttranslational protein modifications in protein aggregation and neurodegenerative diseases.
    Tim Baldensperger, Miriam Preissler, Christian F W Becker.
      Highly reactive metabolic intermediates and other small molecules frequently react with amino acid side chains, leading to non-enzymatic posttranslational modifications (nPTMs) of proteins. The abundance of these modifications increases under high metabolic activity or stress conditions and can dramatically impact protein structure and function. Although protein quality control mechanisms typically mitigate the effects of these impaired proteins, in long-lived and degradation-resistant proteins, nPTMs accumulate. In some cases, such as cataract development and diabetes, clear links between nPTMs, aging, and disease progression have been established. In neurodegenerative diseases such as Alzheimer's and Parkinson's disease, a key question is whether accumulation of nPTMs is a cause or consequence of protein aggregation. This review focuses on major nPTMs found on proteins with central roles in neurodegenerative diseases such as α-synuclein, β-amyloid, and tau. We summarize current knowledge on the formation of these modifications and discuss their potential impact on disease onset and progression. Additionally, we examine what is known to date about how nPTMs impair cellular detoxification, repair, and degradation systems. Finally, we critically discuss the available methodologies to systematically investigate nPTMs at the molecular level and outline suitable approaches to study their effects on protein aggregation. We aim to foster more research into the role of nPTMs in neurodegeneration by adapting methodologies that have proven successful in studying enzymatic posttranslational modifications. Specifically, we advocate for site-specific incorporation of these modifications into target proteins using advanced chemical and molecular biology techniques.
    DOI:  https://doi.org/10.1039/d4cb00221k
  5. Metabolites. 2024 Dec 18. pii: 711. [Epub ahead of print]14(12):
    The Mitochondrial Blueprint: Unlocking Secondary Metabolite Production.
    Yang Li, Yujia Zhang, Xinyu He, Ziyi Guo, Ning Yang, Guohui Bai, Juanjuan Zhao, Delin Xu.
      Mitochondrial metabolism plays a pivotal role in regulating the synthesis of secondary metabolites, which are crucial for the survival and adaptation of organisms. These metabolites are synthesized during specific growth stages or in response to environmental stress, reflecting the organism's ability to adapt to changing conditions. Mitochondria, while primarily known for their role in energy production, directly regulate secondary metabolite biosynthesis by providing essential precursor molecules, energy, and reducing equivalents necessary for metabolic reactions. Furthermore, they indirectly influence secondary metabolism through intricate signaling pathways, including reactive oxygen species (ROS), metabolites, and redox signaling, which modulate various metabolic processes. This review explores recent advances in understanding the molecular mechanisms governing mitochondrial metabolism and their regulatory roles in secondary metabolite biosynthesis, which highlights the involvement of transcription factors, small RNAs, and post-translational mitochondrial modifications in shaping these processes. By integrating current insights, it aims to inspire future research into mitochondrial regulatory mechanisms in Arabidopsis thaliana, Solanum tuberosum, Nicotiana tabacum, and others that may enhance their secondary metabolite production. A deeper understanding of the roles of mitochondria in secondary metabolism could contribute to the development of new approaches in biotechnology applications.
    Keywords:  biosynthesis; mitochondria; regulation mechanism; secondary metabolites; signaling pathway
    DOI:  https://doi.org/10.3390/metabo14120711
  6. Mol Cell. 2024 Dec 17. pii: S1097-2765(24)00990-0. [Epub ahead of print]
    Formyl-methionine-mediated eukaryotic ribosome quality control pathway for cold adaptation.
    Chang-Seok Lee, Jaehwan Sim, Sang-Yoon Kim, Hyeonji Lee, Tae-Young Roh, Cheol-Sang Hwang.
      Protein synthesis in the eukaryotic cytosol can start using both conventional methionine and formyl-methionine (fMet). However, a mechanism, if such exists, for detecting and regulating the incorporation of fMet (instead of Met) during translation, thereby preventing cellular toxicity of nascent fMet-bearing (fMet-) polypeptides, remains unknown. Here, we describe the fMet-mediated ribosome quality control (fMet-RQC) pathway in Saccharomyces cerevisiae. A eukaryotic translation initiation factor 3 subunit c, Nip1, specifically recognizes N-terminal fMet in nascent polypeptides, recruiting a small GTPase, Arf1, to induce ribosome stalling, largely with 41-residue fMet-peptidyl tRNAs. This leads to ribosome dissociation and subsequent stress granule formation. Loss of the fMet-RQC pathway causes the continued synthesis of fMet polypeptides, which inhibits essential N-terminal Met modifications and promotes their coaggregation with ribosomes. This fMet-RQC pathway is important for the adaptation of yeast cells to cold stress by promoting stress granule formation and preventing a buildup of toxic fMet polypeptides.
    Keywords:  Arf1; Nip1; cellular adaptation; cold stress; formyl-methionine; proteotoxicity; ribosome quality control; stress granule
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.035
  7. Metabolites. 2024 Dec 12. pii: 701. [Epub ahead of print]14(12):
    Acetylation-Mediated Post-Translational Modification of Pyruvate Dehydrogenase Plays a Critical Role in the Regulation of the Cellular Acetylome During Metabolic Stress.
    Aishwarya Rajakumar, Sarah Nguyen, Nicole Ford, Gbenga Ogundipe, Ethan Lopez-Nowak, Olena Kondrachuk, Manish K Gupta.
      Background: Cardiac diseases remain one of the leading causes of death globally, often linked to ischemic conditions that can affect cellular homeostasis and metabolism, which can lead to the development of cardiovascular dysfunction. Considering the effect of ischemic cardiomyopathy on the global population, it is vital to understand the impact of ischemia on cardiac cells and how ischemic conditions change different cellular functions through post-translational modification of cellular proteins. Methods: To understand the cellular function and fine-tuning during stress, we established an ischemia model using neonatal rat ventricular cardiomyocytes. Further, the level of cellular acetylation was determined by Western blotting and affinity chromatography coupled with liquid chromatography-mass spectroscopy. Results: Our study found that the level of cellular acetylation significantly reduced during ischemic conditions compared to normoxic conditions. Further, in mass spectroscopy data, 179 acetylation sites were identified in the proteins in ischemic cardiomyocytes. Among them, acetylation at 121 proteins was downregulated, and 26 proteins were upregulated compared to the control groups. Differentially, acetylated proteins are mainly involved in cellular metabolism, sarcomere structure, and motor activity. Additionally, a protein enrichment study identified that the ischemic condition impacted two major biological pathways: the acetyl-CoA biosynthesis process from pyruvate and the tricarboxylic acid cycle by deacetylation of the associated proteins. Moreover, most differential acetylation was found in the protein pyruvate dehydrogenase complex. Conclusions: Understanding the differential acetylation of cellular protein during ischemia may help to protect against the harmful effect of ischemia on cellular metabolism and cytoskeleton organization. Additionally, our study can help to understand the fine-tuning of proteins at different sites during ischemia.
    Keywords:  acetylation; cardiomyocytes; ischemia; metabolism; mitochondria; post-translational modification; pyruvate dehydrogenase complex; ryanodine receptor 3
    DOI:  https://doi.org/10.3390/metabo14120701
  8. Redox Biol. 2024 Dec 16. pii: S2213-2317(24)00442-7. [Epub ahead of print]79 103464
    Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases.
    Ana I Rojo, Brigitta Buttari, Susana Cadenas, Ana Rita Carlos, Antonio Cuadrado, Ana Sofia Falcão, Manuela G López, Milen I Georgiev, Anna Grochot-Przeczek, Sentiljana Gumeni, José Jimenez-Villegas, Jarosław Olav Horbanczuk, Ozlen Konu, Isabel Lastres-Becker, Anna-Liisa Levonen, Viktorija Maksimova, Charalambos Michaeloudes, Liliya V Mihaylova, Michel Edwar Mickael, Irina Milisav, Biljana Miova, Patricia Rada, Marlene Santos, Miguel C Seabra, Dubravka Svob Strac, Sandra Tenreiro, Ioannis P Trougakos, Albena T Dinkova-Kostova.
      Non-communicable chronic diseases (NCDs) are most commonly characterized by age-related loss of homeostasis and/or by cumulative exposures to environmental factors, which lead to low-grade sustained generation of reactive oxygen species (ROS), chronic inflammation and metabolic imbalance. Nuclear factor erythroid 2-like 2 (NRF2) is a basic leucine-zipper transcription factor that regulates the cellular redox homeostasis. NRF2 controls the expression of more than 250 human genes that share in their regulatory regions a cis-acting enhancer termed the antioxidant response element (ARE). The products of these genes participate in numerous functions including biotransformation and redox homeostasis, lipid and iron metabolism, inflammation, proteostasis, as well as mitochondrial dynamics and energetics. Thus, it is possible that a single pharmacological NRF2 modulator might mitigate the effect of the main hallmarks of NCDs, including oxidative, proteostatic, inflammatory and/or metabolic stress. Research on model organisms has provided tremendous knowledge of the molecular mechanisms by which NRF2 affects NCDs pathogenesis. This review is a comprehensive summary of the most commonly used model organisms of NCDs in which NRF2 has been genetically or pharmacologically modulated, paving the way for drug development to combat NCDs. We discuss the validity and use of these models and identify future challenges.
    Keywords:  Inflammation; Model organisms; NRF2; Non-communicable chronic diseases; Oxidative stress
    DOI:  https://doi.org/10.1016/j.redox.2024.103464
  9. Eur J Pharmacol. 2024 Dec 21. pii: S0014-2999(24)00910-5. [Epub ahead of print]988 177220
    Phosphatidic acid as a cofactor of mTORC1 in platinum-based chemoresistance: Mechanisms and therapeutic potential.
    Hadi Alizadeh, Sana Kerachian, Keyvan Jabbari, Bahram Mohammad Soltani.
      Platinum-based chemotherapeutics, such as cisplatin and carboplatin, are widely used to treat various malignancies. However, the development of chemoresistance remains a significant challenge, limiting their efficacy. This review explores the multifaceted mechanisms of platinum-based chemoresistance, with a particular focus on the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, which plays a critical role in promoting tumor survival and resistance to platinum compounds. Additionally, we examined the role of phosphatidic acid (PA) and its synthesizing enzymes, phospholipase D (PLD) and lysophosphatidic acid acyltransferase (LPAAT), in the regulation of mTORC1 activity. Given the involvement of mTORC1 in chemoresistance, we evaluated the potential of mTOR inhibitors as a therapeutic strategy to overcome platinum resistance. Finally, we discuss combination therapies targeting the mTOR pathway alongside conventional chemotherapy to improve treatment outcomes. This review highlights the potential of targeting mTORC1 and related pathways to improve therapeutic strategies for chemoresistant cancers.
    Keywords:  Phosphatidic acid; Platinum-based chemoresistance; mTOR inhibitors; mTORC1
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177220
  10. Pharmacol Ther. 2024 Dec 22. pii: S0163-7258(24)00207-9. [Epub ahead of print] 108787
    Essential role of sulfide oxidation in brain health and neurological disorders.
    Eiki Kanemaru, Fumito Ichinose.
      Hydrogen sulfide (H2S) is an environmental hazard well known for its neurotoxicity. In mammalian cells, H2S is predominantly generated by transsulfuration pathway enzymes. In addition, H2S produced by gut microbiome significantly contributes to the total sulfide burden in the body. Although low levels of H2S is believed to exert various physiological functions such as neurotransmission and vasomotor control, elevated levels of H2S inhibit the activity of cytochrome c oxidase (i.e., mitochondrial complex IV), thereby impairing oxidative phosphorylation. To protect the electron transport chain from respiratory poisoning by H2S, the compound is actively oxidized to form persulfides and polysulfides by a mitochondrial resident sulfide oxidation pathway. The reaction, catalyzed by sulfide:quinone oxidoreductase (SQOR), is the initial and critical step in sulfide oxidation. The persulfide species are subsequently oxidized to sulfite, thiosulfate, and sulfate by persulfide dioxygenase (ETHE1 or SDO), thiosulfate sulfurtransferase (TST), and sulfite oxidase (SUOX). While SQOR is abundantly expressed in the colon, liver, lung, and skeletal muscle, its expression is notably low in the brains of most mammals. Consequently, the brain's limited capacity to oxidize H2S renders it particularly sensitive to the deleterious effects of H2S accumulation. Impaired sulfide oxidation can lead to fatal encephalopathy, and the overproduction of H2S has been implicated in the developmental delays observed in Down syndrome. Our recent findings indicate that the brain's limited capacity to oxidize sulfide exacerbates its sensitivity to oxygen deprivation. The beneficial effects of sulfide oxidation are likely to be mediated not only by the detoxification of H2S but also by the formation of persulfide, which exerts cytoprotective effects through multiple mechanisms. Therefore, pharmacological agents designed to scavenge H2S and/or enhance persulfide levels may offer therapeutic potential against neurological disorders characterized by impaired or insufficient sulfide oxidation or excessive H2S production.
    Keywords:  Hydrogen sulfide; Neurological disorder; Persulfide; Sulfur metabolism
    DOI:  https://doi.org/10.1016/j.pharmthera.2024.108787
  11. FEBS J. 2024 Dec 21.
    Bacterial purine metabolism modulates C. elegans development and stress tolerance via DAF-16.
    Min Feng, Baizhen Gao, L Rene Garcia, Qing Sun.
      The purine metabolism is crucial for cellular function and is a conserved metabolic network from prokaryotes to humans. While extensively studied in microorganisms like yeast and bacteria, the impact of perturbing dietary intermediates from the purine biosynthesis on animal development and growth remains poorly understood. We utilized Caenorhabditis elegans as the metazoan model to investigate the mechanisms underlying this deficiency. Through a high-throughput screening of an Escherichia coli mutant library Keio collection, we identified 34 E. coli mutants that delay C. elegans development. Among these mutants, we found that E. coli purE gene is an essential genetic component that promotes host development in a dose-dependent manner. Further metabolites supplementation suggests that bacterial purE downstream metabolite 5-aminoimidazole-4-carboxamide ribotide (AICAR) can inhibit worm growth. Additionally, we found the FoxO transcription factor DAF-16 is indispensable in worm development delay induced by purE mutation, and observed increased nuclear accumulation of DAF-16 when fed E. coli purE- mutants, suggesting the role of DAF-16 in response to purE mutation. RNA-seq analysis and phenotypic assays revealed that worms fed the E. coli purE mutant exhibited elevated lifespan, thermotolerance, and pathogen resistance. These findings collectively suggest that certain intermediates in the bacterial purine biosynthesis can serve as a cue to modulate development and activate the defense response in the nematode C. elegans through DAF-16.
    Keywords:  C. elegans; DAF‐16; development; purine metabolism; stress tolerance
    DOI:  https://doi.org/10.1111/febs.17363
  12. Metabolites. 2024 Dec 13. pii: 703. [Epub ahead of print]14(12):
    Influence of the Microbial Metabolite Acetyl Phosphate on Mitochondrial Functions Under Conditions of Exogenous Acetylation and Alkalization.
    Natalia V Beloborodova, Nadezhda I Fedotcheva.
       BACKGROUND: Acetyl phosphate (AcP) is a microbial intermediate involved in the central bacterial metabolism. In bacteria, it also functions as a donor of acetyl and phosphoryl groups in the nonenzymatic protein acetylation and signal transduction. In host, AcP was detected as an intermediate of the pyruvate dehydrogenase complex, and its appearance in the blood was considered as an indication of mitochondrial breakdown. In vitro experiments showed that AcP is a powerful agent of nonenzymatic acetylation of proteins. The influence of AcP on isolated mitochondria has not been previously studied.
    METHODS: In this work, we tested the influence of AcP on the opening of the mitochondrial permeability transition pore (mPTP), respiration, and succinate dehydrogenase (SDH) activity under neutral and alkaline conditions stimulating the nonenzymatic acetylation using polarographic, cation-selective, and spectrophotometric methods.
    RESULTS: It was found that AcP slowed down the opening of the mPTP by calcium ions and decreased the efficiency of oxidative phosphorylation and the activity of SDH. These effects were observed only at neutral pH, whereas alkaline pH by itself caused a decrease in these functions to a much greater extent than AcP. AcP at a concentration of 0.5-1 mM decreased the respiratory control and the swelling rate by 20-30%, while alkalization decreased them twofold, thereby masking the effect of AcP. Presumably, the acetylation of adenine nucleotide translocase involved in both the opening of mPTP and oxidative phosphorylation underlies these changes. The intermediate electron carrier phenazine methosulfate (PMS), removing SDH inhibition at the ubiquinone-binding site, strongly activated SDH under alkaline conditions and, partially, in the presence of AcP. It can be assumed that AcP weakly inhibits the oxidation of succinate, while alkalization slows down the electron transfer from the substrate to the acceptor.
    CONCLUSIONS: The results show that both AcP and alkalization, by promoting nonmetabolic and nonenzymatic acetylation from the outside, retard mitochondrial functions.
    Keywords:  acetyl phosphate; adenine nucleotide translocase; alkalization; mitochondrial permeability transition pore; nonenzymatic acetylation; respiration; succinate dehydrogenase
    DOI:  https://doi.org/10.3390/metabo14120703
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