bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒03‒20
twelve papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Role of the TOM Complex in Protein Import into Mitochondria: Structural Views.
  2. Copper induces cell death by targeting lipoylated TCA cycle proteins.
  3. Copper-induced cell death.
  4. Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress.
  5. Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor.
  6. Parallel kinase pathways stimulate actin polymerization at depolarized mitochondria.
  7. Disruption of Mitochondrial Quality Control Genes Promotes Caspase-Resistant Cell Survival Following Apoptotic Stimuli.
  8. Phosphorylation and acetylation of mitochondrial transcription factor A promote transcription processivity without compromising initiation or DNA compaction.
  9. Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells.
  10. Mitochondrial depolarization after acute ethanol treatment drives mitophagy in living mice.
  11. A role for cell polarity in lifespan and mitochondrial quality control in the budding yeast Saccharomyces cerevisiae.
  12. SPOTting stress at the mitochondrial outer membrane.
  1. Annu Rev Biochem. 2022 Feb 14.
    Role of the TOM Complex in Protein Import into Mitochondria: Structural Views.
    Yuhei Araiso, Kenichiro Imai, Toshiya Endo.
      Mitochondria are central to energy production, metabolism and signaling, and apoptosis. To make new mitochondria from preexisting mitochondria, the cell needs to import mitochondrial proteins from the cytosol into the mitochondria with the aid of translocators in the mitochondrial membranes. The translocase of the outer membrane (TOM) complex, an outer membrane translocator, functions as an entry gate for most mitochondrial proteins. Although high-resolution structures of the receptor subunits of the TOM complex were deposited in the early 2000s, those of entire TOM complexes became available only in 2019. The structural details of these TOM complexes, consisting of the dimer of the β-barrel import channel Tom40 and four α-helical membrane proteins, revealed the presence of several distinct paths and exits for the translocation of over 1,000 different mitochondrial precursor proteins. High-resolution structures of TOM complexes now open up a new era of studies on the structures, functions, and dynamics of the mitochondrial import system. Expected final online publication date for the Annual Review of Biochemistry, Volume 91 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biochem-032620-104527
  2. Science. 2022 Mar 18. 375(6586): 1254-1261
    Copper induces cell death by targeting lipoylated TCA cycle proteins.
    Peter Tsvetkov, Shannon Coy, Boryana Petrova, Margaret Dreishpoon, Ana Verma, Mai Abdusamad, Jordan Rossen, Lena Joesch-Cohen, Ranad Humeidi, Ryan D Spangler, John K Eaton, Evgeni Frenkel, Mustafa Kocak, Steven M Corsello, Svetlana Lutsenko, Naama Kanarek, Sandro Santagata, Todd R Golub.
      Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.
    DOI:  https://doi.org/10.1126/science.abf0529
  3. Science. 2022 Mar 18. 375(6586): 1231-1232
    Copper-induced cell death.
    Martha A Kahlson, Scott J Dixon.
      Excess copper causes mitochondrial protein aggregation and triggers a distinct form of cell death.
    DOI:  https://doi.org/10.1126/science.abo3959
  4. Nat Commun. 2022 Mar 14. 13(1): 1300
    Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress.
    Kihyoun Park, Hyejin Lim, Jinyoung Kim, Yeseong Hwang, Yu Seol Lee, Soo Han Bae, Hyeongseok Kim, Hail Kim, Shin-Wook Kang, Joo Young Kim, Myung-Shik Lee.
      Although autophagy is critical for pancreatic β-cell function, the role and mechanism of mitophagy in β-cells are unclear. We studied the role of lysosomal Ca2+ in TFEB activation by mitochondrial or metabolic stress and that of TFEB-mediated mitophagy in β-cell function. Mitochondrial or metabolic stress induced mitophagy through lysosomal Ca2+ release, increased cytosolic Ca2+ and TFEB activation. Lysosomal Ca2+ replenishment by ER- > lysosome Ca2+ refilling was essential for mitophagy. β-cell-specific Tfeb knockout (TfebΔβ-cell) abrogated high-fat diet (HFD)-induced mitophagy, accompanied by increased ROS and reduced mitochondrial cytochrome c oxidase activity or O2 consumption. TfebΔβ-cell mice showed aggravation of HFD-induced glucose intolerance and impaired insulin release. Metabolic or mitochondrial stress induced TFEB-dependent expression of mitophagy receptors including Ndp52 and Optn, contributing to the increased mitophagy. These results suggest crucial roles of lysosomal Ca2+ release coupled with ER- > lysosome Ca2+ refilling and TFEB activation in mitophagy and maintenance of pancreatic β-cell function during metabolic stress.
    DOI:  https://doi.org/10.1038/s41467-022-28874-9
  5. Nat Commun. 2022 Mar 17. 13(1): 1426
    Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor.
    Federico Miozzo, Eva P Valencia-Alarcón, Luca Stickley, Michaëla Majcin Dorcikova, Francesco Petrelli, Damla Tas, Nicolas Loncle, Irina Nikonenko, Peter Bou Dib, Emi Nagoshi.
      Progressive degeneration of dopaminergic (DA) neurons in the substantia nigra is a hallmark of Parkinson's disease (PD). Dysregulation of developmental transcription factors is implicated in dopaminergic neurodegeneration, but the underlying molecular mechanisms remain largely unknown. Drosophila Fer2 is a prime example of a developmental transcription factor required for the birth and maintenance of midbrain DA neurons. Using an approach combining ChIP-seq, RNA-seq, and genetic epistasis experiments with PD-linked genes, here we demonstrate that Fer2 controls a transcriptional network to maintain mitochondrial structure and function, and thus confers dopaminergic neuroprotection against genetic and oxidative insults. We further show that conditional ablation of Nato3, a mouse homolog of Fer2, in differentiated DA neurons causes mitochondrial abnormalities and locomotor impairments in aged mice. Our results reveal the essential and conserved role of Fer2 homologs in the mitochondrial maintenance of midbrain DA neurons, opening new perspectives for modeling and treating PD.
    DOI:  https://doi.org/10.1038/s41467-022-29075-0
  6. Curr Biol. 2022 Mar 08. pii: S0960-9822(22)00328-1. [Epub ahead of print]
    Parallel kinase pathways stimulate actin polymerization at depolarized mitochondria.
    Tak Shun Fung, Rajarshi Chakrabarti, Jana Kollasser, Klemens Rottner, Theresia E B Stradal, Frieda Kage, Henry N Higgs.
      Mitochondrial damage (MtD) represents a dramatic change in cellular homeostasis, necessitating metabolic changes and stimulating mitophagy. One rapid response to MtD is a rapid peri-mitochondrial actin polymerization termed ADA (acute damage-induced actin). The activation mechanism for ADA is unknown. Here, we use mitochondrial depolarization or the complex I inhibitor metformin to induce ADA. We show that two parallel signaling pathways are required for ADA. In one pathway, increased cytosolic calcium in turn activates PKC-β, Rac, WAVE regulatory complex, and Arp2/3 complex. In the other pathway, a drop in cellular ATP in turn activates AMPK (through LKB1), Cdc42, and FMNL formins. We also identify putative guanine nucleotide exchange factors for Rac and Cdc42, Trio and Fgd1, respectively, whose phosphorylation states increase upon mitochondrial depolarization and whose suppression inhibits ADA. The depolarization-induced calcium increase is dependent on the mitochondrial sodium-calcium exchanger NCLX, suggesting initial mitochondrial calcium efflux. We also show that ADA inhibition results in enhanced mitochondrial shape changes upon mitochondrial depolarization, suggesting that ADA inhibits these shape changes. These depolarization-induced shape changes are not fragmentation but a circularization of the inner mitochondrial membrane, which is dependent on the inner mitochondrial membrane protease Oma1. ADA inhibition increases the proteolytic processing of an Oma1 substrate, the dynamin GTPase Opa1. These results show that ADA requires the combined action of the Arp2/3 complex and formin proteins to polymerize a network of actin filaments around mitochondria and that the ADA network inhibits the rapid mitochondrial shape changes that occur upon mitochondrial depolarization.
    Keywords:  AMPK; Arp2/3 complex; CCCP; FMNL formins; OMA1; OPA1; PKCβ; actin; calcium; mitochondrial depolarization
    DOI:  https://doi.org/10.1016/j.cub.2022.02.058
  7. J Biol Chem. 2022 Mar 15. pii: S0021-9258(22)00275-7. [Epub ahead of print] 101835
    Disruption of Mitochondrial Quality Control Genes Promotes Caspase-Resistant Cell Survival Following Apoptotic Stimuli.
    Yulia Kushnareva, Vivian Moraes, Julian Suess, Bjoern Peters, Donald D Newmeyer, Tomomi Kuwana.
      In cells undergoing cell-intrinsic apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically marks an irreversible step in the cell death process. However, in some cases a subpopulation of treated cells can exhibit a sublethal response, termed "minority MOMP". In this phenomenon, the affected cells survive, despite a low level of caspase activation and subsequent limited activation of the endonuclease CAD (DFFB). Consequently, these cells can experience DNA damage, increasing the probability of oncogenesis. However, little is known about the minority MOMP response. To discover genes that affect the MOMP response in individual cells, we conducted an imaging-based phenotypic siRNA screen. We identified multiple candidate genes whose downregulation increased the heterogeneity of MOMP within single cells, among which were genes related to mitochondrial dynamics and mitophagy that participate in the mitochondrial quality control (MQC) system. Furthermore, to test the hypothesis that functional MQC is important for reducing the frequency of minority MOMP, we developed an assay to measure the clonogenic survival of caspase-engaged cells. We found that cells deficient in various MQC genes were indeed prone to aberrant post-MOMP survival. Our data highlight the important role of proteins involved in mitochondrial dynamics and mitophagy in preventing apoptotic dysregulation and oncogenesis.
    Keywords:  apoptosis; mitochondrial dynamics; mitochondrial heterogeneity; mitochondrial outer membrane permeabilization; mitochondrial quality control; mitophagy; oncogenesis; siRNA screen
    DOI:  https://doi.org/10.1016/j.jbc.2022.101835
  8. J Biol Chem. 2022 Mar 09. pii: S0021-9258(22)00255-1. [Epub ahead of print] 101815
    Phosphorylation and acetylation of mitochondrial transcription factor A promote transcription processivity without compromising initiation or DNA compaction.
    Sean D Reardon, Tatiana V Mishanina.
      Mitochondrial transcription factor A (TFAM) plays important roles in mitochondrial DNA (mtDNA) compaction, transcription initiation, and in the regulation of processes like transcription and replication processivity. It is possible that TFAM is locally regulated within the mitochondrial matrix via such mechanisms like phosphorylation by protein kinase A (PKA) and non-enzymatic acetylation by acetyl-CoA. Here we demonstrate that DNA-bound TFAM is less susceptible to these modifications. We confirmed using electrophoretic mobility shift assays that phosphorylated or acetylated TFAM compacted circular double-stranded DNA just as well as unmodified TFAM and provide an in-depth analysis of acetylated sites on TFAM. We show that both modifications of TFAM increase the processivity of mitochondrial RNA polymerase during transcription through TFAM-imposed barriers on DNA, but that TFAM bearing either modification retains its full activity in transcription initiation. We conclude that TFAM phosphorylation by PKA and non-enzymatic acetylation by acetyl-CoA are unlikely to occur at the mtDNA and that modified free TFAM retains its vital functionalities like compaction and transcription initiation while enhancing transcription processivity.
    Keywords:  Acetylation; DNA compaction; Mitochondrial transcription; Phosphorylation
    DOI:  https://doi.org/10.1016/j.jbc.2022.101815
  9. FEBS Open Bio. 2022 Mar 18.
    Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells.
    Oro Uchenunu, Alexander V Zhdanov, Phillipe Hutton, Predrag Jovanovic, Ye Wang, Dmitry E Andreev, Laura Hulea, David J Papadopoli, Daina Avizonis, Pavel V Baranov, Michael N Pollak, Dmitri B Papkovsky, Ivan Topisirovic.
      Mutations in genes encoding cytochrome c oxidase (COX; mitochondrial complex IV) subunits and assembly factors (e.g., SCO1, SCO2, COA6) are linked to severe metabolic syndromes. Notwithstanding that SCO2 is under transcriptional control of tumour suppressor p53, the role of mitochondrial complex IV dysfunction in cancer metabolism remains obscure. Herein, we demonstrate that the loss of SCO2 in HCT116 colorectal cancer cells leads to significant metabolic and signaling perturbations. Specifically, abrogation of SCO2 increased NAD+ regenerating reactions and decreased glucose oxidation through citric acid cycle while enhancing pyruvate carboxylation. This was accompanied by a reduction in amino acid levels and the accumulation of lipid droplets. In addition, SCO2 loss resulted in hyperactivation of the IGF1R/AKT axis with paradoxical downregulation of mTOR signaling which was accompanied by increased AMPK activity. Accordingly, abrogation of SCO2 expression appears to increase the sensitivity of cells to IGF1R and AKT, but not mTOR inhibitors. Finally, the loss of SCO2 was associated with reduced proliferation and enhanced migration of HCT116 cells. Collectively, herein we describe potential adaptive signaling and metabolic perturbations triggered by mitochondrial complex IV dysfunction.
    Keywords:  AKT; AMPK; SCO2; cytochrome C oxidase; mTOR; metabolism; mitochondrial dysfunction
    DOI:  https://doi.org/10.1002/2211-5463.13398
  10. Autophagy. 2022 Mar 16. 1-15
    Mitochondrial depolarization after acute ethanol treatment drives mitophagy in living mice.
    Devadoss J Samuvel, Li Li, Yasodha Krishnasamy, Monika Gooz, Kenji Takemoto, Patrick M Woster, John J Lemasters, Zhi Zhong.
      Ethanol increases hepatic mitophagy driven by unknown mechanisms. Type 1 mitophagy sequesters polarized mitochondria for nutrient recovery and cytoplasmic remodeling. In Type 2, mitochondrial depolarization (mtDepo) initiates mitophagy to remove the damaged organelles. Previously, we showed that acute ethanol administration produces reversible hepatic mtDepo. Here, we tested the hypothesis that ethanol-induced mtDepo initiates Type 2 mitophagy. GFP-LC3 transgenic mice were gavaged with ethanol (2-6 g/kg) with and without pre-treatment with agents that decrease or increase mtDepo-Alda-1, tacrolimus, or disulfiram. Without ethanol, virtually all hepatocytes contained polarized mitochondria with infrequent autophagic GFP-LC3 puncta visualized by intravital microscopy. At ~4 h after ethanol treatment, mtDepo occurred in an all-or-none fashion within individual hepatocytes, which increased dose dependently. GFP-LC3 puncta increased in parallel, predominantly in hepatocytes with mtDepo. Mitochondrial PINK1 and PRKN/parkin also increased. After covalent labeling of mitochondria with MitoTracker Red (MTR), GFP-LC3 puncta encircled MTR-labeled mitochondria after ethanol treatment, directly demonstrating mitophagy. GFP-LC3 puncta did not associate with fat droplets visualized with BODIPY558/568, indicating that increased autophagy was not due to lipophagy. Before ethanol administration, rhodamine-dextran (RhDex)-labeled lysosomes showed little association with GFP-LC3. After ethanol treatment, TFEB (transcription factor EB) translocated to nuclei, and lysosomal mass increased. Many GFP-LC3 puncta merged with RhDex-labeled lysosomes, showing autophagosomal processing into lysosomes. After ethanol treatment, disulfiram increased, whereas Alda-1 and tacrolimus decreased mtDepo, and mitophagy changed proportionately. In conclusion, mtDepo after acute ethanol treatment induces mitophagic sequestration and subsequent lysosomal processing.Abbreviations : AcAld, acetaldehyde; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; ALD, alcoholic liver disease; Alda-1, N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; LAMP1, lysosomal-associated membrane protein 1; LMNB1, lamin B1; MAA, malondialdehyde-acetaldehyde adducts; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MPT, mitochondrial permeability transition; mtDAMPS, mitochondrial damage-associated molecular patterns; mtDepo, mitochondrial depolarization; mtDNA, mitochondrial DNA; MTR, MitoTracker Red; PI, propidium iodide; PINK1, PTEN induced putative kinase 1; PRKN, parkin; RhDex, rhodamine dextran; TFEB, transcription factor EB; Tg, transgenic; TMRM, tetramethylrhodamine methylester; TOMM20, translocase of outer mitochondrial membrane 20; VDAC, voltage-dependent anion channel.
    Keywords:  Acetaldehyde; Alda-1; alcoholic liver disease; mitochondrial depolarization; mitophagy; tacrolimus
    DOI:  https://doi.org/10.1080/15548627.2022.2046457
  11. iScience. 2022 Mar 18. 25(3): 103957
    A role for cell polarity in lifespan and mitochondrial quality control in the budding yeast Saccharomyces cerevisiae.
    Emily J Yang, Wolfgang M Pernice, Liza A Pon.
      Babies are born young, largely independent of the age of their mothers. Mother-daughter age asymmetry in yeast is achieved, in part, by inheritance of higher-functioning mitochondria by buds and retention of some high-functioning mitochondria in mother cells. The mitochondrial F box protein, Mfb1p, tethers mitochondria at both poles in a cell cycle-regulated manner: it localizes to and anchors mitochondria at the mother cell tip throughout the cell cycle and at the bud tip before cytokinesis. Here, we report that cell polarity and polarized localization of Mfb1p decline with age in Saccharomyces cerevisiae. Moreover, deletion of genes (BUD1, BUD2, and BUD5) that mediate symmetry breaking during establishment of cell polarity and asymmetric yeast cell division cause depolarized Mfb1p localization and defects in mitochondrial distribution and quality control. Our results support a role for the polarity machinery in lifespan through modulating Mfb1 function in asymmetric inheritance of mitochondria during yeast cell division.
    Keywords:  Biological sciences; Cell biology; Genetics; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.103957
  12. Mol Cell. 2022 Mar 17. pii: S1097-2765(22)00168-X. [Epub ahead of print]82(6): 1086-1088
    SPOTting stress at the mitochondrial outer membrane.
    Max-Hinderk Schuler, Adam L Hughes.
      Li et al. (2022) discover that Toxoplasma infection triggers remodeling of the mitochondrial outer membrane through generation of a mitochondrial subdomain termed "structure positive for outer mitochondrial membrane" (SPOT).
    DOI:  https://doi.org/10.1016/j.molcel.2022.02.030
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