bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023–09–03
ten papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.
  2. Mitochondrial double membrane fission: A mystery solved?
  3. Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α.
  4. A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.
  5. Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.
  6. The malate-aspartate shuttle is important for de novo serine biosynthesis.
  7. Global determinants of insect mitochondrial genetic diversity.
  8. Spotlight on GOT2 in Cancer Metabolism.
  9. Mitochondrial phospholipid metabolism in health and disease.
  10. Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy.
  1. Cell. 2023 Aug 21. pii: S0092-8674(23)00862-0. [Epub ahead of print]
    PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.
    Ruoxi Wang, Tina M Fortier, Fei Chai, Guangyan Miao, James L Shen, Lucas J Restrepo, Jeromy J DiGiacomo, Panagiotis D Velentzas, Eric H Baehrecke.
      Selective clearance of organelles, including endoplasmic reticulum (ER) and mitochondria, by autophagy plays an important role in cell health. Here, we describe a developmentally programmed selective ER clearance by autophagy. We show that Parkinson's disease-associated PINK1, as well as Atl, Rtnl1, and Trp1 receptors, regulate ER clearance by autophagy. The E3 ubiquitin ligase Parkin functions downstream of PINK1 and is required for mitochondrial clearance while having the opposite function in ER clearance. By contrast, Keap1 and the E3 ubiquitin ligase Cullin3 function downstream of PINK1 to regulate ER clearance by influencing Rtnl1 and Atl. PINK1 regulates a change in Keap1 localization and Keap1-dependent ubiquitylation of the ER-phagy receptor Rtnl1 to facilitate ER clearance. Thus, PINK1 regulates the selective clearance of ER and mitochondria by influencing the balance of Keap1- and Parkin-dependent ubiquitylation of substrates that determine which organelle is removed by autophagy.
    Keywords:  Drosophila; ER-phagy; Keap1; PINK1; Parkin; Rtnl1
    DOI:  https://doi.org/10.1016/j.cell.2023.08.008
  2. J Cell Biol. 2023 Oct 02. pii: e202308119. [Epub ahead of print]222(10):
    Mitochondrial double membrane fission: A mystery solved?
    Benedikt Westermann.
      It has long been an unresolved question whether the division machineries that assemble on the mitochondrial surface cooperate with factors inside the organelle. Now, two studies by Connor et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202303147) and Fukuda et al. (2023. Mol. Cell.https://doi.org/10.1016/j.molcel.2023.04.022) have identified an intermembrane space protein that is crucial for mitochondrial double membrane division.
    DOI:  https://doi.org/10.1083/jcb.202308119
  3. Proc Natl Acad Sci U S A. 2023 Sep 05. 120(36): e2302360120
    Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α.
    Laura M de Smalen, Anastasiya Börsch, Aurel B Leuchtmann, Jonathan F Gill, Danilo Ritz, Mihaela Zavolan, Christoph Handschin.
      Sarcopenia, the age-related loss of skeletal muscle mass and function, can dramatically impinge on quality of life and mortality. While mitochondrial dysfunction and imbalanced proteostasis are recognized as hallmarks of sarcopenia, the regulatory and functional link between these processes is underappreciated and unresolved. We therefore investigated how mitochondrial proteostasis, a crucial process that coordinates the expression of nuclear- and mitochondrial-encoded mitochondrial proteins with supercomplex formation and respiratory activity, is affected in skeletal muscle aging. Intriguingly, a robust mitochondrial translation impairment was observed in sarcopenic muscle, which is regulated by the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) with the estrogen-related receptor α (ERRα). Exercise, a potent inducer of PGC-1α activity, rectifies age-related reduction in mitochondrial translation, in conjunction with quality control pathways. These results highlight the importance of mitochondrial proteostasis in muscle aging, and elucidate regulatory interactions that underlie the powerful benefits of physical activity in this context.
    Keywords:  aging; mitochondria; proteostasis; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1073/pnas.2302360120
  4. Nat Metab. 2023 Aug 31.
    A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.
    Undiagnosed Diseases Network
      In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism. Mutations in human MECR cause pediatric-onset neurodegeneration, and we show that human-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study identifies a role of mecr/MECR in ceramide and iron metabolism, providing a mechanistic link between mtFAS and neurodegeneration.
    DOI:  https://doi.org/10.1038/s42255-023-00873-0
  5. Cell Metab. 2023 Aug 22. pii: S1550-4131(23)00289-9. [Epub ahead of print]
    Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.
    Dusanka Milenkovic, Jelena Misic, Johannes F Hevler, Thibaut Molinié, Injae Chung, Ilian Atanassov, Xinping Li, Roberta Filograna, Andrea Mesaros, Arnaud Mourier, Albert J R Heck, Judy Hirst, Nils-Göran Larsson.
      The mammalian respiratory chain complexes I, III2, and IV (CI, CIII2, and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI-CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and the regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knockin mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in mice but raise questions about their alternate functions, such as those relating to the regulation of protein stability and prevention of age-associated protein aggregation.
    Keywords:  OXPHOS; mitochondria; mitochondrial respirasomes; supercomplexes
    DOI:  https://doi.org/10.1016/j.cmet.2023.07.015
  6. Cell Rep. 2023 Aug 29. pii: S2211-1247(23)01054-9. [Epub ahead of print]42(9): 113043
    The malate-aspartate shuttle is important for de novo serine biosynthesis.
    Melissa H Broeks, Nils W F Meijer, Denise Westland, Marjolein Bosma, Johan Gerrits, Hannah M German, Jolita Ciapaite, Clara D M van Karnebeek, Ronald J A Wanders, Fried J T Zwartkruis, Nanda M Verhoeven-Duif, Judith J M Jans.
      The malate-aspartate shuttle (MAS) is a redox shuttle that transports reducing equivalents across the inner mitochondrial membrane while recycling cytosolic NADH to NAD+. We genetically disrupted each MAS component to generate a panel of MAS-deficient HEK293 cell lines in which we performed [U-13C]-glucose tracing. MAS-deficient cells have reduced serine biosynthesis, which strongly correlates with the lactate M+3/pyruvate M+3 ratio (reflective of the cytosolic NAD+/NADH ratio), consistent with the NAD+ dependency of phosphoglycerate dehydrogenase in the serine synthesis pathway. Among the MAS-deficient cells, those lacking malate dehydrogenase 1 (MDH1) show the most severe metabolic disruptions, whereas oxoglutarate-malate carrier (OGC)- and MDH2-deficient cells are less affected. Increasing the NAD+-regenerating capacity using pyruvate supplementation resolves most of the metabolic disturbances. Overall, we show that the MAS is important for de novo serine biosynthesis, implying that serine supplementation could be used as a therapeutic strategy for MAS defects and possibly other redox disorders.
    Keywords:  CP: Metabolism; NADH shuttle; central carbon metabolism; glycolysis; isotope-tracer analysis; malate dehydrogenase; malate-aspartate shuttle; metabolomics; serine biosynthesis
    DOI:  https://doi.org/10.1016/j.celrep.2023.113043
  7. Nat Commun. 2023 Aug 29. 14(1): 5276
    Global determinants of insect mitochondrial genetic diversity.
    Connor M French, Laura D Bertola, Ana C Carnaval, Evan P Economo, Jamie M Kass, David J Lohman, Katharine A Marske, Rudolf Meier, Isaac Overcast, Andrew J Rominger, Phillip P A Staniczenko, Michael J Hickerson.
      Understanding global patterns of genetic diversity is essential for describing, monitoring, and preserving life on Earth. To date, efforts to map macrogenetic patterns have been restricted to vertebrates, which comprise only a small fraction of Earth's biodiversity. Here, we construct a global map of predicted insect mitochondrial genetic diversity from cytochrome c oxidase subunit 1 sequences, derived from open data. We calculate the mitochondrial genetic diversity mean and genetic diversity evenness of insect assemblages across the globe, identify their environmental correlates, and make predictions of mitochondrial genetic diversity levels in unsampled areas based on environmental data. Using a large single-locus genetic dataset of over 2 million globally distributed and georeferenced mtDNA sequences, we find that mitochondrial genetic diversity evenness follows a quadratic latitudinal gradient peaking in the subtropics. Both mitochondrial genetic diversity mean and evenness positively correlate with seasonally hot temperatures, as well as climate stability since the last glacial maximum. Our models explain 27.9% and 24.0% of the observed variation in mitochondrial genetic diversity mean and evenness in insects, respectively, making an important step towards understanding global biodiversity patterns in the most diverse animal taxon.
    DOI:  https://doi.org/10.1038/s41467-023-40936-0
  8. Onco Targets Ther. 2023 ;16 695-702
    Spotlight on GOT2 in Cancer Metabolism.
    Samuel A Kerk, Javier Garcia-Bermudez, Kivanc Birsoy, Mara H Sherman, Yatrik M Shah, Costas A Lyssiotis.
      GOT2 is at the nexus of several critical metabolic pathways in homeostatic cellular and dysregulated cancer metabolism. Despite this, recent work has emphasized the remarkable plasticity of cancer cells to employ compensatory pathways when GOT2 is inhibited. Here, we review the metabolic roles of GOT2, highlighting findings in both normal and cancer cells. We emphasize how cancer cells repurpose cell intrinsic metabolism and their flexibility when GOT2 is inhibited. We close by using this framework to discuss key considerations for future investigations into cancer metabolism.
    Keywords:  mitochondria; nucleotides; pancreatic cancer; redox; transaminase; tumor microenvironment
    DOI:  https://doi.org/10.2147/OTT.S382161
  9. J Cell Sci. 2023 Sep 01. pii: jcs260857. [Epub ahead of print]136(17):
    Mitochondrial phospholipid metabolism in health and disease.
    Alaumy Joshi, Travis H Richard, Vishal M Gohil.
      Studies of rare human genetic disorders of mitochondrial phospholipid metabolism have highlighted the crucial role that membrane phospholipids play in mitochondrial bioenergetics and human health. The phospholipid composition of mitochondrial membranes is highly conserved from yeast to humans, with each class of phospholipid performing a specific function in the assembly and activity of various mitochondrial membrane proteins, including the oxidative phosphorylation complexes. Recent studies have uncovered novel roles of cardiolipin and phosphatidylethanolamine, two crucial mitochondrial phospholipids, in organismal physiology. Studies on inter-organellar and intramitochondrial phospholipid transport have significantly advanced our understanding of the mechanisms that maintain mitochondrial phospholipid homeostasis. Here, we discuss these recent advances in the function and transport of mitochondrial phospholipids while describing their biochemical and biophysical properties and biosynthetic pathways. Additionally, we highlight the roles of mitochondrial phospholipids in human health by describing the various genetic diseases caused by disruptions in their biosynthesis and discuss advances in therapeutic strategies for Barth syndrome, the best-studied disorder of mitochondrial phospholipid metabolism.
    Keywords:  Barth syndrome; Cardiolipin; Membranes; Mitochondria; Phosphatidylethanolamine; Phospholipids
    DOI:  https://doi.org/10.1242/jcs.260857
  10. Biomed Pharmacother. 2023 Aug 24. pii: S0753-3322(23)01133-2. [Epub ahead of print]166 115342
    Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy.
    Yongjian Guo, Chengju Luo, Yuening Sun, Wenjing Guo, Ruitian Zhang, Xin Zhang, Xue Ke, Libin Wei.
      Mitochondria dynamically change their morphology via fusion and fission, a process called mitochondrial dynamics. Dysregulated mitochondrial dynamics respond rapidly to metabolic cues, and are linked to the initiation and progression of diverse human cancers. Metabolic adaptations significantly contribute to tumor development and escape from tissue homeostatic defenses. In this work, we identified oroxylin A (OA), a dual GLUT1/mitochondrial fusion inhibitor, which restricted glucose catabolism of hepatocellular carcinoma cells and simultaneously inhibited mitochondrial fusion by disturbing SIRT1/PDK2/PARL axis. Based the dual action of OA in metabolic regulation and mitochondrial dynamics, further results revealed that mitochondrial functional status and spare respiratory capacity (SRC) of cancer cells had a close correlation with mitochondrial metabolic plasticity, and played important roles in the susceptibility to cancer therapy aiming at glucose restriction. Cancer cells with healthy mitochondria and high SRC exhibit greater metabolic flexibility and higher resistance to GLUT1 inhibitors. This phenomenon is attributed to the fact that high SRC cells fuse mitochondria in response to glucose restriction, enhancing tolerance to energy deficiency, but undergo less mitochondrial oxidative stress compared to low SRC cells. Thus, inhibiting mitochondrial fusion breaks mitochondrial metabolic plasticity and increases cancer cell susceptibility to glucose restriction therapy. Collectively, these finding indicate that combining a GLUT1 inhibitor with a mitochondrial fusion inhibitor can work synergistically in cancer therapy and, more broadly, suggest that the incorporations of mitochondrial dynamics and metabolic regulation may become the targetable vulnerabilities bypassing the genotypic heterogeneity of multiple malignancies.
    Keywords:  Glucose restriction; Mitochondrial fusion; Mitochondrial metabolic plasticity; Oroxylin A
    DOI:  https://doi.org/10.1016/j.biopha.2023.115342
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