bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2021–08–01
twelve papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes.
  2. Super-resolution microscopy reveals the arrangement of inner membrane protein complexes in mammalian mitochondria.
  3. Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by Cardiolipin-interacting small molecules.
  4. Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1.
  5. Mitochondrial fusion and fission are required for proper mitochondrial function and cell proliferation in fission yeast.
  6. SNX19 restricts endolysosome motility through contacts with the endoplasmic reticulum.
  7. Monitoring selective autophagy of mitochondria using super-resolution microscopy.
  8. Loss of the mitochondrial phosphate carrier SLC25A3 induces remodeling of the cardiac mitochondrial protein acylome.
  9. Polycystin-1 regulates cardiomyocyte mitophagy.
  10. Mitochondrial regulation of ferroptosis.
  11. Move it to lose it: Mitocytosis expels damaged mitochondria.
  12. MDVs to the rescue: How autophagy-deficient cancer cells adapt to defective mitophagy.
  1. Cell Rep. 2021 Jul 27. pii: S2211-1247(21)00864-0. [Epub ahead of print]36(4): 109447
    Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes.
    Byung Soo Kong, Se Hee Min, Changhan Lee, Young Min Cho.
      Mitochondria are principal metabolic organelles that are increasingly unveiled as immune regulators. However, it is currently not known whether mitochondrial-encoded peptides modulate T cells to induce changes in phenotype and function. In this study, we found that MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) prevented autoimmune β cell destruction by targeting T cells in non-obese diabetic (NOD) mice. MOTS-c ameliorated the development of hyperglycemia and reduced islet-infiltrating immune cells. Furthermore, adoptive transfer of T cells from MOTS-c-treated NOD mice significantly decreased the incidence of diabetes in NOD-severe combined immunodeficiency (SCID) mice. Metabolic and genomic analyses revealed that MOTS-c modulated T cell phenotype and function by regulating T cell receptor (TCR)/mTOR complex 1 (mTORC1) signaling. Type 1 diabetes (T1D) patients had a lower serum MOTS-c level than did healthy controls. Furthermore, MOTS-c reduced T cell activation by alleviating T cells from the glycolytic stress in T1D patients, suggesting therapeutic potential. Our findings indicate that MOTS-c regulates the T cell phenotype and suppresses autoimmune diabetes.
    Keywords:  CD4(+) T cell; Foxp3; IFNγ; MOTS-c; T cell activation; T cell differentiation; T(reg); mTORC1; mitochondria; type 1 diabetes
    DOI:  https://doi.org/10.1016/j.celrep.2021.109447
  2. J Cell Sci. 2021 07 01. pii: jcs252197. [Epub ahead of print]134(13):
    Super-resolution microscopy reveals the arrangement of inner membrane protein complexes in mammalian mitochondria.
    Catherine S Palmer, Jieqiong Lou, Betty Kouskousis, Elvis Pandzic, Alexander J Anderson, Yilin Kang, Elizabeth Hinde, Diana Stojanovski.
      The mitochondrial inner membrane is a protein-rich environment containing large multimeric complexes, including complexes of the mitochondrial electron transport chain, mitochondrial translocases and quality control machineries. Although the inner membrane is highly proteinaceous, with 40-60% of all mitochondrial proteins localised to this compartment, little is known about the spatial distribution and organisation of complexes in this environment. We set out to survey the arrangement of inner membrane complexes using stochastic optical reconstruction microscopy (STORM). We reveal that subunits of the TIM23 complex, TIM23 and TIM44 (also known as TIMM23 and TIMM44, respectively), and the complex IV subunit COXIV, form organised clusters and show properties distinct from the outer membrane protein TOM20 (also known as TOMM20). Density based cluster analysis indicated a bimodal distribution of TIM44 that is distinct from TIM23, suggesting distinct TIM23 subcomplexes. COXIV is arranged in larger clusters that are disrupted upon disruption of complex IV assembly. Thus, STORM super-resolution microscopy is a powerful tool for examining the nanoscale distribution of mitochondrial inner membrane complexes, providing a 'visual' approach for obtaining pivotal information on how mitochondrial complexes exist in a cellular context.
    Keywords:  COXIV; Mitochondria; Mitochondrial complexes; Nanoscopy; Protein import; STORM; TIM23
    DOI:  https://doi.org/10.1242/jcs.252197
  3. J Biol Chem. 2021 Jul 24. pii: S0021-9258(21)00807-3. [Epub ahead of print] 101005
    Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by Cardiolipin-interacting small molecules.
    Arianna F Anzmann, Olivia L Sniezek, Alexandra Pado, Veronica Busa, Frédéric M Vaz, Simion D Kreimer, Lauren R DeVine, Robert N Cole, Anne Le, Brian J Kirsch, Steven M Claypool, Hilary J Vernon.
      Barth syndrome (BTHS) is an X-linked disorder of mitochondrial phospholipid metabolism caused by pathogenic variants in the gene TAFFAZIN (TAZ), which results in abnormal cardiolipin (CL) content in the inner mitochondrial membrane. To identify unappreciated pathways of mitochondrial dysfunction in BTHS, we utilized an unbiased proteomics strategy and identified that complex I of the mitochondrial respiratory chain and the mitochondrial quality control protease PARL are altered in a new HEK293-based TAZ-deficiency model. Follow-up studies confirmed decreased steady state levels of specific complex I subunits and an assembly factor in the absence of TAZ; this decrease is in part based on decreased transcription, and results in reduced complex I assembly and function. PARL, a rhomboid protease associated with the inner mitochondrial membrane with a role in the mitochondrial response to stress such as mitochondrial membrane depolarization, is increased in TAZ-deficient cells. The increased abundance of PARL correlates with augmented processing of a downstream target, PGAM5, both at baseline and in response to mitochondrial depolarization. To clarify the relationship between abnormal CL content, complex I levels, and increased PARL expression that occurs when TAZ is missing, we used blue-native page and gene expression analysis to determine that these defects are remediated by SS-31 and bromoenol lactone, pharmacologic agents that bind CL or inhibit CL deacylation, respectively. These findings have the potential to enhance our understanding of the cardiac pathology of BTHS, where defective mitochondrial quality control and complex I dysfunction have well-recognized roles in the pathology of diverse forms of cardiac dysfunction.
    Keywords:  Barth Syndrome; Cardiolipin; Mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2021.101005
  4. JCI Insight. 2021 Jul 27. pii: 147692. [Epub ahead of print]
    Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1.
    Yang Cao, Lingyi Tang, Kang Du, Kitt Paraiso, Qiushi Sun, Zhengxia Liu, Xiaolong Ye, Yuan Fang, Fang Yuan, Yu-Han Chen, Yumay Chen, Xiaorong Wang, Clinton Yu, Ira L Blitz, Ping H Wang, Lan Huang, Haibo Cheng, Xiang Lu, Ken Wy Cho, Marcus Seldin, Zhuyuan Fang, Qin Yang.
      Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than one thousand nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain to be fully elucidated. Here we show that histone demethylase LSD1 knockout from adult mouse liver (LSD1-LKO) reduces the expression of one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 regulates gene expression and protein methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), which controls the final step of NAD+ synthesis and limits NAD+ availability in nucleus. Lsd1 knockout reduces NAD+-dependent SIRT1 and SIRT7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABPβ and PGC-1α, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function in liver, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.
    Keywords:  Diabetes; Endocrinology; Obesity
    DOI:  https://doi.org/10.1172/jci.insight.147692
  5. FEBS J. 2021 Jul 26.
    Mitochondrial fusion and fission are required for proper mitochondrial function and cell proliferation in fission yeast.
    Fenfen Dong, Mengdan Zhu, Fan Zheng, Chuanhai Fu.
      Mitochondria form a branched tubular network in many types of cells, depending on a balance between mitochondrial fusion and fission. How mitochondrial fusion and fission are involved in regulating mitochondrial function and cell proliferation is not well understood. Here, we dissected the roles of mitochondrial fusion and fission in mitochondrial function and cell proliferation in fission yeast. We examined mitochondrial membrane potential by staining cells with DiOC6 and assessed mitochondrial respiration by directly measuring oxygen consumption of cells with a dissolved oxygen respirometer. We found that defects in mitochondrial fission or fusion reduce mitochondrial membrane potential and compromise mitochondrial respiration while the absence of both mitochondrial fusion and fission restores wild-type-like respiration, normal membrane potential, and tubular networks of mitochondria. Moreover, we found that the absence of either mitochondrial fission or fusion prolongs the cell cycle and that the absence of both mitochondrial fusion and fission significantly delays cell cycle progression after nitrogen replenishment. The prolonged/delayed cell cycle is likely due to the deregulation of Cdc2 activation. Hence, our work not only establishes an intimate link between mitochondrial morphology and function but also underscores the importance of mitochondrial dynamics in regulating the cell cycle.
    Keywords:  Cell cycle; Dnm1; Fzo1; Mitochondria; Mitochondrial dynamics
    DOI:  https://doi.org/10.1111/febs.16138
  6. Nat Commun. 2021 07 27. 12(1): 4552
    SNX19 restricts endolysosome motility through contacts with the endoplasmic reticulum.
    Amra Saric, Spencer A Freeman, Chad D Williamson, Michal Jarnik, Carlos M Guardia, Michael S Fernandopulle, David C Gershlick, Juan S Bonifacino.
      The ability of endolysosomal organelles to move within the cytoplasm is essential for the performance of their functions. Long-range movement involves coupling of the endolysosomes to motor proteins that carry them along microtubule tracks. This movement is influenced by interactions with other organelles, but the mechanisms involved are incompletely understood. Herein we show that the sorting nexin SNX19 tethers endolysosomes to the endoplasmic reticulum (ER), decreasing their motility and contributing to their concentration in the perinuclear area of the cell. Tethering depends on two N-terminal transmembrane domains that anchor SNX19 to the ER, and a PX domain that binds to phosphatidylinositol 3-phosphate on the endolysosomal membrane. Two other domains named PXA and PXC negatively regulate the interaction of SNX19 with endolysosomes. These studies thus identify a mechanism for controlling the motility and positioning of endolysosomes that involves tethering to the ER by a sorting nexin.
    DOI:  https://doi.org/10.1038/s41467-021-24709-1
  7. Methods Cell Biol. 2021 ;pii: S0091-679X(20)30193-X. [Epub ahead of print]165 153-161
    Monitoring selective autophagy of mitochondria using super-resolution microscopy.
    Ziyue Li, Nicholas T Ktistakis.
      Selective elimination of damaged mitochondria via macroautophagy (mitophagy) is a conserved cellular process that plays an important role in organismal health. In recent years mitophagy has been studied in parallel to the more general, non-selective autophagy pathway induced in response to amino acid starvation with important similarities and differences noted between the two. The elaborate sequence of membrane rearrangements that give rise to autophagosomes in the non-selective pathway have their counterpart in mitophagy, but with the addition of other factors, such as a ubiquitin mark and mitophagy receptors, which mediate cargo recognition. In some types of mitophagy such as the one induced by ivermectin, the forming autophagosomal structure contains six different elements: the targeted mitochondrial fragment, a section of endoplasmic reticulum that provides a cradle, a ubiquitin layer, the mitophagy receptors and the early and late autophagosomal proteins/membranes. Super-resolution microscopy is ideally suited to investigate the spatial relationships between these elements that converge together but retain some distinctive localization, and we provide here a general protocol that can be used for mammalian cells.
    Keywords:  Autophagy; Endoplasmic reticulum; Ivermectin; Mitochondria; Mitophagy; Structured illumination microscopy
    DOI:  https://doi.org/10.1016/bs.mcb.2020.10.010
  8. Am J Physiol Cell Physiol. 2021 07 28.
    Loss of the mitochondrial phosphate carrier SLC25A3 induces remodeling of the cardiac mitochondrial protein acylome.
    Jessica N Peoples, Nasab Ghazal, Duc M Duong, Katherine R Hardin, Janet R Manning, Nicholas T Seyfried, Victor Faundez, Jennifer Q Kwong.
      Mitochondria are recognized as signaling organelles because, under stress, mitochondria can trigger various signaling pathways to coordinate the cell's response. The specific pathway(s) engaged by mitochondria in response to mitochondrial energy defects in vivo and in high-energy tissues like the heart are not fully understood. Here, we investigated cardiac pathways activated in response to mitochondrial energy dysfunction by studying mice with cardiomyocyte-specific loss of the mitochondrial phosphate carrier (SLC25A3), an established model that develops cardiomyopathy as a result of defective mitochondrial ATP synthesis. Mitochondrial energy dysfunction induced a striking pattern of acylome remodeling, with significantly increased post-translational acetylation and malonylation. Mass spectrometry-based proteomics further revealed that energy dysfunction-induced remodeling of the acetylome and malonylome preferentially impacts mitochondrial proteins. Acetylation and malonylation modified a highly interconnected interactome of mitochondrial proteins, and both modifications were present on the enzyme isocitrate dehydrogenase 2 (IDH2). Intriguingly, IDH2 activity was enhanced in SLC25A3-deleted mitochondria, and further study of IDH2 sites targeted by both acetylation and malonylation revealed that these modifications can have site-specific and distinct functional effects. Finally, we uncovered a novel crosstalk between the two modifications, whereby mitochondrial energy dysfunction-induced acetylation of sirtuin 5 (SIRT5), inhibited its function. Because SIRT5 is a mitochondrial deacylase with demalonylase activity, this finding suggests that acetylation can modulate the malonylome. Together, our results position acylations as an arm of the mitochondrial response to energy dysfunction and suggest a mechanism by which focal disruption to the energy production machinery can have an expanded impact on global mitochondrial function.
    Keywords:  acetylation; acylations; energy; heart; mitochondria
    DOI:  https://doi.org/10.1152/ajpcell.00156.2021
  9. FASEB J. 2021 Aug;35(8): e21796
    Polycystin-1 regulates cardiomyocyte mitophagy.
    Andrea Ramírez-Sagredo, Clara Quiroga, Valeria Garrido-Moreno, Camila López-Crisosto, Sebastian Leiva-Navarrete, Ignacio Norambuena-Soto, Jafet Ortiz-Quintero, Magda C Díaz-Vesga, William Perez, Troy Hendrickson, Valentina Parra, Zully Pedrozo, Francisco Altamirano, Mario Chiong, Sergio Lavandero.
      Polycystin-1 (PC1) is a transmembrane protein found in different cell types, including cardiomyocytes. Alterations in PC1 expression have been linked to mitochondrial damage in renal tubule cells and in patients with autosomal dominant polycystic kidney disease. However, to date, the regulatory role of PC1 in cardiomyocyte mitochondria is not well understood. The analysis of mitochondrial morphology from cardiomyocytes of heterozygous PC1 mice (PDK1+/- ) using transmission electron microscopy showed that cardiomyocyte mitochondria were smaller with increased mitochondria density and circularity. These parameters were consistent with mitochondrial fission. We knocked-down PC1 in cultured rat cardiomyocytes and human-induced pluripotent stem cells (iPSC)-derived cardiomyocytes to evaluate mitochondrial function and morphology. The results showed that downregulation of PC1 expression results in reduced protein levels of sub-units of the OXPHOS complexes and less functional mitochondria (reduction of mitochondrial membrane potential, mitochondrial respiration, and ATP production). This mitochondrial dysfunction activates the elimination of defective mitochondria by mitophagy, assessed by an increase of autophagosome adapter protein LC3B and the recruitment of the Parkin protein to the mitochondria. siRNA-mediated PC1 knockdown leads to a loss of the connectivity of the mitochondrial network and a greater number of mitochondria per cell, but of smaller sizes, which characterizes mitochondrial fission. PC1 silencing also deregulates the AKT-FoxO1 signaling pathway, which is involved in the regulation of mitochondrial metabolism, mitochondrial morphology, and processes that are part of cell quality control, such as mitophagy. Together, these data provide new insights about the controls that PC1 exerts on mitochondrial morphology and function in cultured cardiomyocytes dependent on the AKT-FoxO1 signaling pathway.
    Keywords:  FoxO1; cardiomyocyte; mitochondrial dynamics; mitochondrial metabolism; mitophagy; polycystin-1
    DOI:  https://doi.org/10.1096/fj.202002598R
  10. J Cell Biol. 2021 Sep 06. pii: e202105043. [Epub ahead of print]220(9):
    Mitochondrial regulation of ferroptosis.
    Boyi Gan.
      Ferroptosis is a form of iron-dependent regulated cell death driven by uncontrolled lipid peroxidation. Mitochondria are double-membrane organelles that have essential roles in energy production, cellular metabolism, and cell death regulation. However, their role in ferroptosis has been unclear and somewhat controversial. In this Perspective, I summarize the diverse metabolic processes in mitochondria that actively drive ferroptosis, discuss recently discovered mitochondria-localized defense systems that detoxify mitochondrial lipid peroxides and protect against ferroptosis, present new evidence for the roles of mitochondria in regulating ferroptosis, and outline outstanding questions on this fascinating topic for future investigations. An in-depth understanding of mitochondria functions in ferroptosis will have important implications for both fundamental cell biology and disease treatment.
    DOI:  https://doi.org/10.1083/jcb.202105043
  11. Dev Cell. 2021 Jul 26. pii: S1534-5807(21)00546-3. [Epub ahead of print]56(14): 2014-2015
    Move it to lose it: Mitocytosis expels damaged mitochondria.
    Chahat Mehra, Lena Pernas.
      Mechanisms by which cells remove damaged mitochondria extracellularly are unclear. Recent work by Jiao and colleagues in Cell shows that migrating cells expel dysfunctional mitochondria in membrane-bound structures called migrasomes to maintain mitochondrial homeostasis.
    DOI:  https://doi.org/10.1016/j.devcel.2021.07.001
  12. Dev Cell. 2021 Jul 26. pii: S1534-5807(21)00529-3. [Epub ahead of print]56(14): 2010-2012
    MDVs to the rescue: How autophagy-deficient cancer cells adapt to defective mitophagy.
    Laura Poillet-Perez, Eileen White.
      Cancers are dependent on mitochondria, the powerhouse of the cell, and autophagy, the mechanism to preserve mitochondrial quality and function. In this issue of Developmental Cell, Towers et al. identify mitochondria-derived vesicles (MDVs) as a new adaptive mechanism enabling cancer cells to compensate for autophagy loss and to maintain mitochondrial function.
    DOI:  https://doi.org/10.1016/j.devcel.2021.06.022
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