bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2020‒08‒09
fourteen papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Heme Synthesis Inhibition Blocks Angiogenesis via Mitochondrial Dysfunction.
  2. Mitochondrial volume fraction and translation duration impact mitochondrial mRNA localization and protein synthesis.
  3. The Lon Protease Links Nucleotide Metabolism with Proteotoxic Stress.
  4. Aster-B Coordinates with Arf1 to Regulate Mitochondrial Cholesterol Transport.
  5. Altered MICOS Morphology and Mitochondrial Ion Homeostasis Contribute to Poly(GR) Toxicity Associated with C9-ALS/FTD.
  6. Mitochondrial morphology and activity regulate furrow ingression and contractile ring dynamics in Drosophila cellularization.
  7. Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter.
  8. Methylation of Ribosomal RNA: A Mitochondrial Perspective.
  9. Pleiotropic effects of mdivi-1 in altering mitochondrial dynamics, respiration, and autophagy in cardiomyocytes.
  10. Miro, a Rho GTPase genetically interacts with Alzheimer's disease-associated genes (Tau, Aβ 42 and Appl) in Drosophila melanogaster.
  11. Safeguarding mitochondrial genomes in higher eukaryotes.
  12. The C-terminal region of the oxidoreductase MIA40 stabilizes its cytosolic precursor during mitochondrial import.
  13. A Vectorial, ER-Mitochondria Link to Energy Homeostasis in the Vascular Endothelium.
  14. Mitochondrial complex I structure reveals ordered water molecules for catalysis and proton translocation.
  1. iScience. 2020 Jul 20. pii: S2589-0042(20)30579-4. [Epub ahead of print]23(8): 101391
    Heme Synthesis Inhibition Blocks Angiogenesis via Mitochondrial Dysfunction.
    Trupti Shetty, Kamakshi Sishtla, Bomina Park, Matthew J Repass, Timothy W Corson.
      The relationship between heme metabolism and angiogenesis is poorly understood. The final synthesis of heme occurs in mitochondria, where ferrochelatase (FECH) inserts Fe2+ into protoporphyrin IX to produce proto-heme IX. We previously showed that FECH inhibition is antiangiogenic in human retinal microvascular endothelial cells (HRECs) and in animal models of ocular neovascularization. In the present study, we sought to understand the mechanism of how FECH and thus heme is involved in endothelial cell function. Mitochondria in endothelial cells had several defects in function after heme inhibition. FECH loss changed the shape and mass of mitochondria and led to significant oxidative stress. Oxidative phosphorylation and mitochondrial Complex IV were decreased in HRECs and in murine retina ex vivo after heme depletion. Supplementation with heme partially rescued phenotypes of FECH blockade. These findings provide an unexpected link between mitochondrial heme metabolism and angiogenesis.
    Keywords:  Cell Biology; Developmental Genetics; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2020.101391
  2. Elife. 2020 Aug 07. pii: e57814. [Epub ahead of print]9
    Mitochondrial volume fraction and translation duration impact mitochondrial mRNA localization and protein synthesis.
    Tatsuhisa Tsuboi, Matheus P Viana, Fan Xu, Jingwen Yu, Raghav Chanchani, Ximena G Arceo, Evelina Tutucci, Joonhyuk Choi, Yang S Chen, Robert H Singer, Susanne M Rafelski, Brian M Zid.
      Mitochondria are dynamic organelles that must precisely control their protein composition according to cellular energy demand. Although nuclear-encoded mRNAs can be localized to the mitochondrial surface, the importance of this localization is unclear. As yeast switch to respiratory metabolism, there is an increase in the fraction of the cytoplasm that is mitochondrial. Our data point to this change in mitochondrial volume fraction increasing the localization of certain nuclear-encoded mRNAs to the surface of the mitochondria. We show that mitochondrial mRNA localization is necessary and sufficient to increase protein production to levels required during respiratory growth. Furthermore, we find that ribosome stalling impacts mRNA sensitivity to mitochondrial volume fraction and counterintuitively leads to enhanced protein synthesis by increasing mRNA localization to mitochondria. This points to a mechanism by which cells are able to use translation elongation and the geometric constraints of the cell to fine-tune organelle-specific gene expression through mRNA localization.
    Keywords:  S. cerevisiae; cell biology; chromosomes; gene expression; mRNA localization; mitochondria; protein synthesis
    DOI:  https://doi.org/10.7554/eLife.57814
  3. Mol Cell. 2020 Jul 28. pii: S1097-2765(20)30477-9. [Epub ahead of print]
    The Lon Protease Links Nucleotide Metabolism with Proteotoxic Stress.
    Rilee D Zeinert, Hamid Baniasadi, Benjamin P Tu, Peter Chien.
      During proteotoxic stress, bacteria maintain critical processes like DNA replication while removing misfolded proteins, which are degraded by the Lon protease. Here, we show that in Caulobacter crescentus Lon controls deoxyribonucleoside triphosphate (dNTP) pools during stress through degradation of the transcription factor CcrM. Elevated dNTP/nucleotide triphosphate (NTP) ratios in Δlon cells protects them from deletion of otherwise essential deoxythymidine triphosphate (dTTP)-producing pathways and shields them from hydroxyurea-induced loss of dNTPs. Increased dNTP production in Δlon results from higher expression of ribonucleotide reductase driven by increased CcrM. We show that misfolded proteins can stabilize CcrM by competing for limited protease and that Lon-dependent control of dNTPs improves fitness during protein misfolding conditions. We propose that linking dNTP production with availability of Lon allows Caulobacter to maintain replication capacity when misfolded protein burden increases, such as during rapid growth. Because Lon recognizes misfolded proteins regardless of the stress, this mechanism allows for response to a variety of unanticipated conditions.
    Keywords:  AAA+ protease; chaperone titration; proteotoxic stress; quality control; transposon sequencing
    DOI:  https://doi.org/10.1016/j.molcel.2020.07.011
  4. Mol Metab. 2020 Jul 29. pii: S2212-8778(20)30129-0. [Epub ahead of print] 101055
    Aster-B Coordinates with Arf1 to Regulate Mitochondrial Cholesterol Transport.
    John-Paul Andersen, Jun Zhang, Haoran Sun, Xuyun Liu, Jiankang Liu, Jia Nie, Yuguang Shi.
      OBJECTIVE: Cholesterol plays a pivotal role in mitochondrial steroidogenesis, membrane structure, and respiration. Mitochondrial membranes are intrinsically low in cholesterol content, and therefore must be replenished with cholesterol from other subcellular membranes. However, the molecular mechanisms underlying mitochondrial cholesterol transport remains poorly understood. The Aster-B gene encodes a cholesterol binding protein recently implicated in cholesterol trafficking from the plasma membrane to the ER. In this study, we investigated the function and underlying mechanism of Aster-B in mediating mitochondrial cholesterol transport.METHODS: CRISPR/Cas9 gene editing was carried out to generate cell lines deficient in Aster-B expression. The effect of Aster-B deficiency on mitochondrial cholesterol transport was examined by both confocal imaging analysis and biochemical assays. Deletion mutational analysis was also carried out to identify the function of a putative mitochondrial targeting sequence (MTS) at the N-terminus of Aster-B for its role in targeting Aster-B to mitochondria and in mediating mitochondrial cholesterol trafficking.
    RESULTS: Ablation of Aster-B impaired cholesterol transport from the ER to mitochondria, leading to a significant decrease in mitochondrial cholesterol content. Aster-B is also required for mitochondrial transport of fatty acids derived from hydrolysis of cholesterol esters. A putative MTS at the N-terminus of Aster-B mediates the mitochondrial cholesterol uptake. Deletion of the MTS or ablation of Arf1 GTPase which is required for mitochondrial translocation of ER proteins prevented mitochondrial cholesterol transport, leading to mitochondrial dysfunction.
    CONCLUSIONS: We identified Aster-B as a key regulator of cholesterol transport from the ER to mitochondria. Aster-B also coordinates mitochondrial cholesterol trafficking with uptake of fatty acids derived from cholesterol ester, implicating the Aster-B protein as a novel regulator of steroidogenesis.
    Keywords:  Arf1; Cholesterol Transport; Fatty Acids; GRAMD1b; Mitochondria
    DOI:  https://doi.org/10.1016/j.molmet.2020.101055
  5. Cell Rep. 2020 Aug 04. pii: S2211-1247(20)30974-8. [Epub ahead of print]32(5): 107989
    Altered MICOS Morphology and Mitochondrial Ion Homeostasis Contribute to Poly(GR) Toxicity Associated with C9-ALS/FTD.
    Shuangxi Li, Zhihao Wu, Yu Li, Ishaq Tantray, Diego De Stefani, Andrea Mattarei, Gopinath Krishnan, Fen-Biao Gao, Hannes Vogel, Bingwei Lu.
      Amyotrophic lateral sclerosis (ALS) manifests pathological changes in motor neurons and various other cell types. Compared to motor neurons, the contribution of the other cell types to the ALS phenotypes is understudied. G4C2 repeat expansion in C9ORF72 is the most common genetic cause of ALS along with frontotemporal dementia (C9-ALS/FTD), with increasing evidence supporting repeat-encoded poly(GR) in disease pathogenesis. Here, we show in Drosophila muscle that poly(GR) enters mitochondria and interacts with components of the Mitochondrial Contact Site and Cristae Organizing System (MICOS), altering MICOS dynamics and intra-subunit interactions. This impairs mitochondrial inner membrane structure, ion homeostasis, mitochondrial metabolism, and muscle integrity. Similar mitochondrial defects are observed in patient fibroblasts. Genetic manipulation of MICOS components or pharmacological restoration of ion homeostasis with nigericin effectively rescue the mitochondrial pathology and disease phenotypes in both systems. These results implicate MICOS-regulated ion homeostasis in C9-ALS pathogenesis and suggest potential new therapeutic strategies.
    Keywords:  C9-ALS/FTD; DPR; K(+)/H(+) antiporter; MICOS; Mic27/Apool; Opa1; cristae junction; mitochondrial K(+) homeostasis; muscle; nigericin
    DOI:  https://doi.org/10.1016/j.celrep.2020.107989
  6. Mol Biol Cell. 2020 Aug 05. mbcE20030177
    Mitochondrial morphology and activity regulate furrow ingression and contractile ring dynamics in Drosophila cellularization.
    Sayali Chowdhary, Somya Madan, Darshika Tomer, Manos Mavrakis, Richa Rikhy.
      Mitochondria are maternally inherited in many organisms. Mitochondrial morphology and activity regulation is essential for cell survival, differentiation and migration. An analysis of mitochondrial dynamics and function in morphogenetic events in early metazoan embryogenesis has not been carried out. In our study we find a crucial role of mitochondrial morphology regulation in cell formation in Drosophila embryogenesis. We find that mitochondria are small, fragmented and translocate apically on microtubules and distribute progressively along the cell length during cellularization. Embryos mutant for mitochondrial fission protein, Drp1, die in embryogenesis and show an accumulation of clustered mitochondria on the basal side in cellularization. Additionally, Drp1 mutant embryos contain lower levels of reactive oxygen species (ROS). ROS depletion has been previously shown to decrease Myosin II activity. Drp1 loss also leads to Myosin II depletion at the membrane furrow thereby resulting in decreased cell height and larger contractile ring area in cellularization similar to Myosin II mutants. The mitochondrial morphology and cellularization defects in Drp1 mutants are suppressed by reducing mitochondrial fusion and increasing cytoplasmic ROS in superoxide dismutase mutants. Our data show a key role for mitochondrial morphology and activity in supporting the morphogenetic events that drive cellularization in Drosophila embryos. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E20-03-0177
  7. Elife. 2020 Aug 07. pii: e60513. [Epub ahead of print]9
    Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter.
    Yan Wang, Yan Han, Ji She, Nam X Nguyen, Vamsi K Mootha, Xiao-Chen Bai, Youxing Jiang.
      Mitochondrial Ca2+ uptake is mediated by an inner mitochondrial membrane protein called the mitochondrial calcium uniporter. In humans, the uniporter functions as a holocomplex consisting of MCU, EMRE, MICU1 and MICU2, among which MCU and EMRE form a subcomplex and function as the conductive channel while MICU1 and MICU2 are EF-hand proteins that regulate the channel activity in a Ca2+ dependent manner. Here we present the EM structures of the human mitochondrial calcium uniporter holocomplex (uniplex) in the presence and absence of Ca2+, revealing distinct Ca2+ dependent assembly of the uniplex. Our structural observations suggest that Ca2+ changes the dimerization interaction between MICU1 and MICU2, which in turn determines how the MICU1-MICU2 subcomplex interacts with the MCU-EMRE channel and, consequently, changes the distribution of the uniplex assemblies between the blocked and unblocked states.
    Keywords:  biochemistry; chemical biology; human; molecular biophysics; structural biology
    DOI:  https://doi.org/10.7554/eLife.60513
  8. Front Genet. 2020 ;11 761
    Methylation of Ribosomal RNA: A Mitochondrial Perspective.
    M Isabel G Lopez Sanchez, Miriam Cipullo, Shreekara Gopalakrishna, Anas Khawaja, Joanna Rorbach.
      Ribosomal RNA (rRNA) from all organisms undergoes post-transcriptional modifications that increase the diversity of its composition and activity. In mitochondria, specialized mitochondrial ribosomes (mitoribosomes) are responsible for the synthesis of 13 oxidative phosphorylation proteins encoded by the mitochondrial genome. Mitoribosomal RNA is also modified, with 10 modifications thus far identified and all corresponding modifying enzymes described. This form of epigenetic regulation of mitochondrial gene expression affects mitoribosome biogenesis and function. Here, we provide an overview on rRNA methylation and highlight critical work that is beginning to elucidate its role in mitochondrial gene expression. Given the similarities between bacterial and mitochondrial ribosomes, we focus on studies involving Escherichia coli and human models. Furthermore, we highlight the use of state-of-the-art technologies, such as cryoEM in the study of rRNA methylation and its biological relevance. Understanding the mechanisms and functional relevance of this process represents an exciting frontier in the RNA biology and mitochondrial fields.
    Keywords:  RNA; epigenetics; methylation; methyltransferases; mitochondria; ribosome
    DOI:  https://doi.org/10.3389/fgene.2020.00761
  9. Redox Biol. 2020 Jul 26. pii: S2213-2317(20)30865-X. [Epub ahead of print]36 101660
    Pleiotropic effects of mdivi-1 in altering mitochondrial dynamics, respiration, and autophagy in cardiomyocytes.
    Richa Aishwarya, Shafiul Alam, Chowdhury S Abdullah, Mahboob Morshed, Sadia S Nitu, Manikandan Panchatcharam, Sumitra Miriyala, Christopher G Kevil, Md Shenuarin Bhuiyan.
      Mitochondria are highly dynamic organelles that constantly undergo fission and fusion events to adapt to changes in the cellular environment. Aberrant mitochondrial fission has been associated with several types of cardiovascular dysfunction; inhibition of pathologically aberrant mitochondrial fission has been shown to be cardioprotective. Pathological fission is mediated by the excessive activation of GTPase dynamin-related protein 1 (Drp1), making it an attractive therapeutic target in numerous cardiovascular diseases. Mitochondrial division inhibitor (mdivi-1) is widely used small molecule reported to inhibit Drp1-dependent fission, elongate mitochondria, and mitigate injury. The purpose of our study was to understand the pleiotropic effects of mdivi-1 on mitochondrial dynamics, mitochondrial respiration, electron transport activities, and macro-autophagy. In this study, we found that mdivi-1 treatment decreased Drp1 expression, proteolytically cleaved L-OPA1, and altered the expression of OXPHOS complex proteins, resulting in increased superoxide production. The altered expression of OXPHOS complex proteins may be directly associated with decreased Drp1 expression, as Drp1 siRNA knockdown in cardiomyocytes showed similar effects. Results from an autophagy flux assay showed that mdivi-1 induced impaired autophagy flux that could be restored by Atg7 overexpression, suggesting that mdivi-1 mediated inhibition of macro-autophagy in cardiomyocytes. Treatment with mdivi-1 resulted in increased expression of p62, which is required for Atg7 overexpression-induced rescue of mdivi-1-mediated impaired autophagy flux. In addition, mdivi-1-dependent proteolytic processing of L-OPA1 was associated with increased mitochondrial superoxide production and altered expression of mitochondrial serine/proteases. Overall, the novel pleiotropic effect of mdivi-1 in cardiomyocytes included proteolytically cleaved L-OPA1, altered expression of OXPHOS complex proteins, and increased superoxide production, which together resulted in defects in mitochondrial respiration and inhibition of macro-autophagy.
    Keywords:  Macro-autophagy; Mitochondria fission; Mitochondrial dysfunction; Mitochondrial proteases; mdivi-1
    DOI:  https://doi.org/10.1016/j.redox.2020.101660
  10. Biol Open. 2020 Aug 03. pii: bio.049569. [Epub ahead of print]
    Miro, a Rho GTPase genetically interacts with Alzheimer's disease-associated genes (Tau, Aβ 42 and Appl) in Drosophila melanogaster.
    Komal Panchal, Anand Krishna Tiwari.
      Miro (mitochondrial Rho GTPases), a mitochondrial outer membrane protein, facilitates mitochondrial axonal transport along the microtubules to facilitate neuronal function. It plays an important role in regulating mitochondrial dynamics (fusion and fission) and cellular energy generation. Thus, Miro might be associated with the key pathologies of several neurodegenerative diseases (NDs) including Alzheimer's disease (AD). In the present manuscript, we have demonstrated the possible genetic interaction between Miro and AD-related genes such as Tau, Aβ 42 and Appl in Drosophila melanogaster Ectopic expression of Tau, Aβ 42 and Appl induced a rough eye phenotype, defects in phototaxis and climbing activity, and shortened lifespan in the flies. In our study, we have observed that overexpression of Miro improves the rough eye phenotype, behavioral activities (climbing and phototaxis) and ATP level in AD model flies. Further, the improvement examined in AD-related phenotypes was correlated with decreased oxidative stress, cell death and neurodegeneration in Miro overexpressing AD model flies. Thus, the obtained results suggested that Miro genetically interacts with AD-related genes in Drosophila and has the potential to be used as a therapeutic target for the design of therapeutic strategies for NDs.
    Keywords:  Alzheimer's disease; Appl; Aβ42; Miro; Mitochondria; Tau
    DOI:  https://doi.org/10.1242/bio.049569
  11. Nat Struct Mol Biol. 2020 Aug;27(8): 687-695
    Safeguarding mitochondrial genomes in higher eukaryotes.
    Yi Fu, Marco Tigano, Agnel Sfeir.
      Mitochondria respond to DNA damage and preserve their own genetic material in a manner distinct from that of the nucleus but that requires organized mito-nuclear communication. Failure to resolve mtDNA breaks leads to mitochondrial dysfunction and affects host cells and tissues. Here, we review the pathways that safeguard mitochondrial genomes and examine the insights gained from studies of cellular and tissue-wide responses to mtDNA damage and mito-nuclear genome incompatibility.
    DOI:  https://doi.org/10.1038/s41594-020-0474-9
  12. BMC Biol. 2020 Aug 06. 18(1): 96
    The C-terminal region of the oxidoreductase MIA40 stabilizes its cytosolic precursor during mitochondrial import.
    Lena Maria Murschall, Anne Gerhards, Thomas MacVicar, Esra Peker, Lidwina Hasberg, Stephan Wawra, Thomas Langer, Jan Riemer.
      BACKGROUND: The mitochondrial intermembrane space (IMS) is home to proteins fulfilling numerous essential cellular processes, particularly in metabolism and mitochondrial function. All IMS proteins are nuclear encoded and synthesized in the cytosol and must therefore be correctly targeted and transported to the IMS, either through mitochondrial targeting sequences or conserved cysteines and the mitochondrial disulfide relay system. The mitochondrial oxidoreductase MIA40, which catalyzes disulfide formation in the IMS, is imported by the combined action of the protein AIFM1 and MIA40 itself. Here, we characterized the function of the conserved highly negatively charged C-terminal region of human MIA40.RESULTS: We demonstrate that the C-terminal region is critical during posttranslational mitochondrial import of MIA40, but is dispensable for MIA40 redox function in vitro and in intact cells. The C-terminal negatively charged region of MIA40 slowed import into mitochondria, which occurred with a half-time as slow as 90 min. During this time, the MIA40 precursor persisted in the cytosol in an unfolded state, and the C-terminal negatively charged region served in protecting MIA40 from proteasomal degradation. This stabilizing property of the MIA40 C-terminal region could also be conferred to a different mitochondrial precursor protein, COX19.
    CONCLUSIONS: Our data suggest that the MIA40 precursor contains the stabilizing information to allow for postranslational import of sufficient amounts of MIA40 for full functionality of the essential disulfide relay. We thereby provide for the first time mechanistic insights into the determinants controlling cytosolic surveillance of IMS precursor proteins.
    Keywords:  Disulfide relay; MIA40; Mitochondrial import; Mitochondrial precursor; Negatively charged C-terminus; Proteasomal degradation
    DOI:  https://doi.org/10.1186/s12915-020-00824-1
  13. Cell Metab. 2020 Aug 04. pii: S1550-4131(20)30368-5. [Epub ahead of print]32(2): 150-152
    A Vectorial, ER-Mitochondria Link to Energy Homeostasis in the Vascular Endothelium.
    Nabil E Boutagy, Joseph W Fowler, William C Sessa.
      The precise mechanisms of free fatty acid (FFA) uptake in the vascular endothelium are unclear. In this issue of Cell Metabolism, Ibrahim et al. (2020) discover that FFA uptake is partially mediated by a vectorial, ER-mitochondria link, in which mitochondrial ATP production is locally used for the acyl-CoA synthetase activity of the ER-located fatty acid transport protein 4.
    DOI:  https://doi.org/10.1016/j.cmet.2020.07.010
  14. Nat Struct Mol Biol. 2020 Aug 03.
    Mitochondrial complex I structure reveals ordered water molecules for catalysis and proton translocation.
    Daniel N Grba, Judy Hirst.
      Mitochondrial complex I powers ATP synthesis by oxidative phosphorylation, exploiting the energy from ubiquinone reduction by NADH to drive protons across the energy-transducing inner membrane. Recent cryo-EM analyses of mammalian and yeast complex I have revolutionized structural and mechanistic knowledge and defined structures in different functional states. Here, we describe a 2.7-Å-resolution structure of the 42-subunit complex I from the yeast Yarrowia lipolytica containing 275 structured water molecules. We identify a proton-relay pathway for ubiquinone reduction and water molecules that connect mechanistically crucial elements and constitute proton-translocation pathways through the membrane. By comparison with known structures, we deconvolute structural changes governing the mammalian 'deactive transition' (relevant to ischemia-reperfusion injury) and their effects on the ubiquinone-binding site and a connected cavity in ND1. Our structure thus provides important insights into catalysis by this enigmatic respiratory machine.
    DOI:  https://doi.org/10.1038/s41594-020-0473-x
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