bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023‒04‒02
nine papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Norovirus MLKL-like protein initiates cell death to induce viral egress.
  2. The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage.
  3. Cytosolic and mitochondrial NADPH fluxes are independently regulated.
  4. Mitochondria-associated membrane protein PACS2 maintains right cardiac function in hypobaric hypoxia.
  5. Mitochondrial DNA Release in Innate Immune Signaling.
  6. Mitochondrial ATP synthase as a direct molecular target of chromium(III) to ameliorate hyperglycaemia stress.
  7. Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease.
  8. The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
  9. Evolution: 'Millefoglie' origin of mitochondrial cristae.
  1. Nature. 2023 Mar 29.
    Norovirus MLKL-like protein initiates cell death to induce viral egress.
    Guoxun Wang, Di Zhang, Robert C Orchard, Dustin C Hancks, Tiffany A Reese.
      Non-enveloped viruses require cell lysis to release new virions from infected cells, suggesting that these viruses require mechanisms to induce cell death. Noroviruses are one such group of viruses, but there is no known mechanism that causes norovirus infection-triggered cell death and lysis1-3. Here we identify a molecular mechanism of norovirus-induced cell death. We found that the norovirus-encoded NTPase NS3 contains an N-terminal four-helix bundle domain homologous to the membrane-disruption domain of the pseudokinase mixed lineage kinase domain-like (MLKL). NS3 has a mitochondrial localization signal and thus induces cell death by targeting mitochondria. Full-length NS3 and an N-terminal fragment of the protein bound the mitochondrial membrane lipid cardiolipin, permeabilized the mitochondrial membrane and induced mitochondrial dysfunction. Both the N-terminal region and the mitochondrial localization motif of NS3 were essential for cell death, viral egress from cells and viral replication in mice. These findings suggest that noroviruses have acquired a host MLKL-like pore-forming domain to facilitate viral egress by inducing mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41586-023-05851-w
  2. Cell Rep. 2023 Mar 31. pii: S2211-1247(23)00343-1. [Epub ahead of print]42(4): 112332
    The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage.
    Pablo Rivera-Mejías, Álvaro Jesús Narbona-Pérez, Lidwina Hasberg, Lara Kroczek, Amir Bahat, Steffen Lawo, Kat Folz-Donahue, Anna-Lena Schumacher, Sofia Ahola, Fiona Carola Mayer, Patrick Giavalisco, Hendrik Nolte, Sergio Lavandero, Thomas Langer.
      The metabolic plasticity of mitochondria ensures cell development, differentiation, and survival. The peptidase OMA1 regulates mitochondrial morphology via OPA1 and stress signaling via DELE1 and orchestrates tumorigenesis and cell survival in a cell- and tissue-specific manner. Here, we use unbiased systems-based approaches to show that OMA1-dependent cell survival depends on metabolic cues. A metabolism-focused CRISPR screen combined with an integrated analysis of human gene expression data found that OMA1 protects against DNA damage. Nucleotide deficiencies induced by chemotherapeutic agents promote p53-dependent apoptosis of cells lacking OMA1. The protective effect of OMA1 does not depend on OMA1 activation or OMA1-mediated OPA1 and DELE1 processing. OMA1-deficient cells show reduced glycolysis and accumulate oxidative phosphorylation (OXPHOS) proteins upon DNA damage. OXPHOS inhibition restores glycolysis and confers resistance against DNA damage. Thus, OMA1 dictates the balance between cell death and survival through the control of glucose metabolism, shedding light on its role in cancerogenesis.
    Keywords:  CP: Metabolism; DNA damage; OMA1; OXPHOS; glucose metabolism; mitochondria; nucleotides; p53
    DOI:  https://doi.org/10.1016/j.celrep.2023.112332
  3. Nat Chem Biol. 2023 Mar 27.
    Cytosolic and mitochondrial NADPH fluxes are independently regulated.
    Xiangfeng Niu, Ethan Stancliffe, Susan J Gelman, Lingjue Wang, Michaela Schwaiger-Haber, Joe L Rowles, Leah P Shriver, Gary J Patti.
      Although nicotinamide adenine dinucleotide phosphate (NADPH) is produced and consumed in both the cytosol and mitochondria, the relationship between NADPH fluxes in each compartment has been difficult to assess due to technological limitations. Here we introduce an approach to resolve cytosolic and mitochondrial NADPH fluxes that relies on tracing deuterium from glucose to metabolites of proline biosynthesis localized to either the cytosol or mitochondria. We introduced NADPH challenges in either the cytosol or mitochondria of cells by using isocitrate dehydrogenase mutations, administering chemotherapeutics or with genetically encoded NADPH oxidase. We found that cytosolic challenges influenced NADPH fluxes in the cytosol but not NADPH fluxes in mitochondria, and vice versa. This work highlights the value of using proline labeling as a reporter system to study compartmentalized metabolism and reveals that NADPH homeostasis in the cytosolic and mitochondrial locations of a cell are independently regulated, with no evidence for NADPH shuttle activity.
    DOI:  https://doi.org/10.1038/s41589-023-01283-9
  4. iScience. 2023 Apr 21. 26(4): 106328
    Mitochondria-associated membrane protein PACS2 maintains right cardiac function in hypobaric hypoxia.
    Jie Yang, Mengjia Sun, Renzheng Chen, Xiaowei Ye, Boji Wu, Zhen Liu, Jihang Zhang, Xubin Gao, Ran Cheng, Chunyan He, Jingyu He, Xuhong Wang, Lan Huang.
      Hypobaric hypoxia (HH) is the primary challenge at highland. Prolonged HH exposure impairs right cardiac function. Mitochondria-associated membrane (MAM) plays a principal role in regulating mitochondrial function under hypoxia, but the mechanism was unclear. In this study, proteomics analysis identified that PACS2, a key protein in MAM, and mitophagy were downregulated in HH. Metabolomics analysis indicated suppression of glucose and fatty acids aerobic oxidation in HH conditions. Cardiomyocyte Pacs2 deficiency disrupted MAM formation and endoplasmic reticulum (ER)-mitochondria calcium flux, further inhibiting mitophagy and energy metabolism in HH. Pacs2 overexpression reversed these effects. Cardiac-specific knockout of Pacs2 exacerbated mitophagy inhibition, cardiomyocyte injury, and right cardiac dysfunction induced by HH. Conditional knock-in of Pacs2 recovered HH-induced right cardiac impairment. Thus, PACS2 is essential for protecting cardiomyocytes through ER-mitochondria calcium flux, mitophagy, and mitochondrial energy metabolism. Our work provides insight into the mechanism of HH-induced cardiomyocyte injury and potential targets for maintaining the right cardiac function at the highland.
    Keywords:  Cardiovascular medicine; Metabolomics; Molecular biology; Physiology; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2023.106328
  5. Annu Rev Biochem. 2023 Mar 31.
    Mitochondrial DNA Release in Innate Immune Signaling.
    Laura E Newman, Gerald S Shadel.
      According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). The ability of mtDNA to escape mitochondria and integrate into the nuclear genome was discovered in budding yeast, along with genes that regulate this process. Mitochondria have emerged as key regulators of innate immunity, and it is now recognized that mtDNA released into the cytoplasm, outside of the cell, or into circulation activates multiple innate immune signaling pathways. Here, we first review the mechanisms through which mtDNA is released into the cytoplasm, including several inducible mitochondrial pores and defective mitophagy or autophagy. Next, we cover how the different forms of released mtDNA activate specific innate immune nucleic acid sensors and inflammasomes. Finally, we discuss how intracellular and extracellular mtDNA release, including circulating cell-free mtDNA that promotes systemic inflammation, are implicated in human diseases, bacterial and viral infections, and senescence and aging. Expected final online publication date for the Annual Review of Biochemistry, Volume 92 is June 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biochem-032620-104401
  6. Nat Commun. 2023 Mar 28. 14(1): 1738
    Mitochondrial ATP synthase as a direct molecular target of chromium(III) to ameliorate hyperglycaemia stress.
    Haibo Wang, Ligang Hu, Hongyan Li, Yau-Tsz Lai, Xueying Wei, Xiaohan Xu, Zhenkun Cao, Huiming Cao, Qianya Wan, Yuen-Yan Chang, Aimin Xu, Qunfang Zhou, Guibin Jiang, Ming-Liang He, Hongzhe Sun.
      Chromium(III) is extensively used as a supplement for muscle development and the treatment of diabetes mellitus. However, its mode of action, essentiality, and physiological/pharmacological effects have been a subject of scientific debate for over half a century owing to the failure in identifying the molecular targets of Cr(III). Herein, by integrating fluorescence imaging with a proteomic approach, we visualized the Cr(III) proteome being mainly localized in the mitochondria, and subsequently identified and validated eight Cr(III)-binding proteins, which are predominately associated with ATP synthesis. We show that Cr(III) binds to ATP synthase at its beta subunit via the catalytic residues of Thr213/Glu242 and the nucleotide in the active site. Such a binding suppresses ATP synthase activity, leading to the activation of AMPK, improving glucose metabolism, and rescuing mitochondria from hyperglycaemia-induced fragmentation. The mode of action of Cr(III) in cells also holds true in type II diabetic male mice. Through this study, we resolve the long-standing question of how Cr(III) ameliorates hyperglycaemia stress at the molecular level, opening a new horizon for further exploration of the pharmacological effects of Cr(III).
    DOI:  https://doi.org/10.1038/s41467-023-37351-w
  7. Nat Commun. 2023 Mar 27. 14(1): 1703
    Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease.
    Themis Thoudam, Dipanjan Chanda, Jung Yi Lee, Min-Kyo Jung, Ibotombi Singh Sinam, Byung-Gyu Kim, Bo-Yoon Park, Woong Hee Kwon, Hyo-Jeong Kim, Myeongjin Kim, Chae Won Lim, Hoyul Lee, Yang Hoon Huh, Caroline A Miller, Romil Saxena, Nicholas J Skill, Nazmul Huda, Praveen Kusumanchi, Jing Ma, Zhihong Yang, Min-Ji Kim, Ji Young Mun, Robert A Harris, Jae-Han Jeon, Suthat Liangpunsakul, In-Kyu Lee.
      Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca2+-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced MCC complex formation and subsequent mitochondrial Ca2+ accumulation and dysfunction. Finally, ectopic induction of MAM formation reverses the protective effect of PDK4 deficiency in alcohol-induced liver injury. Together, our study defines a mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD.
    DOI:  https://doi.org/10.1038/s41467-023-37214-4
  8. Life Sci Alliance. 2023 Jun;pii: e202301914. [Epub ahead of print]6(6):
    The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
    Jana Schuettpelz, Alexandre Janer, Hana Antonicka, Eric A Shoubridge.
      Mutations in SLC25A46 underlie a wide spectrum of neurodegenerative diseases associated with alterations in mitochondrial morphology. We established an SLC25A46 knock-out cell line in human fibroblasts and studied the pathogenicity of three variants (p.T142I, p.R257Q, and p.E335D). Mitochondria were fragmented in the knock-out cell line and hyperfused in all pathogenic variants. The loss of SLC25A46 led to abnormalities in the mitochondrial cristae ultrastructure that were not rescued by the expression of the variants. SLC25A46 was present in discrete puncta at mitochondrial branch points and tips of mitochondrial tubules, co-localizing with DRP1 and OPA1. Virtually, all fission/fusion events were demarcated by a SLC25A46 focus. SLC25A46 co-immunoprecipitated with the fusion machinery, and loss of function altered the oligomerization state of OPA1 and MFN2. Proximity interaction mapping identified components of the ER membrane, lipid transfer proteins, and mitochondrial outer membrane proteins, indicating that it is present at interorganellar contact sites. SLC25A46 loss of function led to altered mitochondrial lipid composition, suggesting that it may facilitate interorganellar lipid flux or play a role in membrane remodeling associated with mitochondrial fusion and fission.
    DOI:  https://doi.org/10.26508/lsa.202301914
  9. Curr Biol. 2023 Mar 27. pii: S0960-9822(23)00177-X. [Epub ahead of print]33(6): R219-R221
    Evolution: 'Millefoglie' origin of mitochondrial cristae.
    Paul A M Michels, Michael L Ginger.
      Striated intracytoplasmic membranes in alphaproteobacteria are often reminiscent of millefoglie pastries. A new study reveals a protein complex homologous to that responsible for mitochondrial cristae formation drives intracytoplasmic membrane formation, thereby establishing bacterial ancestry for the biogenesis of mitochondrial cristae.
    DOI:  https://doi.org/10.1016/j.cub.2023.02.037
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