DOCSLIB.ORG

Snapshot: Mitochondrial Dynamics

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

SnapShot: Mitochondrial Dynamics Yasushi Tamura,1 Kie Itoh,1 and Hiromi Sesaki,1 1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Mitochondrial fusion-division cycle Mitochondrial shape Drp1/Dnm1 Fusion < Division Fusion ≈ Division Fusion > Division Drp1/Dnm1 receptor Fragmented Tubular Elongated Mfn1 and 2/Fzo1 Opa1/Mgm1 MEF Yeast Fragmented with 10 µm 5 µm swollen cristae Enlarged Fusion machinery CYTOSOL Mammals CYTOSOL Yeast Positive regulator for Mfn2 Bax Bcl-xL Mfn1 Mfn2 Ubiquitin ligase for Mfn1 and 2 G Proteasome Negative regulator Ub degraded Parkin Pink1 MITOL/March5 Ub for Mfn1 and 2 G R R MIB Mdm30 Ugo1 OM SCF Fzo1 OM G Ubiquitin ligase IMS G for Fzo1 i-AAA s-Opa1 G IMS G IM s-Mgm1 IM Parl l-Opa1 Oma1 m-AAA Pcp1 l-Mgm1 Processing peptidases Processing peptidases HUMAN DISEASE ASSOCIATION for Mgm1 for Opa1 Mfn2: Charcot-Marie-Tooth type 2A Parkin and Pink1: Parkinson’s disease MATRIX Opa1: Autosomal dominant optic atrophy type 1 MATRIX Division machinery Mammals Yeast Algae CYTOSOL Posttranslational CYTOSOL CYTOSOL modulators for Drp1 PKA CaMKla P Calcineurin Cdk1-cyclin B Cortical actin G G NO G G Dnm1 Dnm1 Senp5 Dnm1 Dnm1 Ub SUMO Mda1 G Mdv1 G MAPL Caf4 Drp1 MITOL/March5 Num1 Dnm1 RR Fis1 R Fis1 Mdm36 OM OM OM GDAP1 IMS IMS Drp1 receptors IMS Mff MiD49/MiD51 IM IM ? Fis1 IM ? FtsZ MATRIX ZED G HUMAN DISEASE ASSOCIATION Drp1: Postneonatal death with neurodevelopmental disorders GDAP1: Charcot-Marie-Tooth type 4A MATRIX MATRIX 1158 Cell 145, June 24, 2011 ©2011 Elsevier Inc. DOI 10.1016/j.cell.2011.06.018 See online version for legend and references. SnapShot: Mitochondrial Dynamics Yasushi Tamura,1 Kie Itoh,1 and Hiromi Sesaki,1 1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Mitochondrial Fusion and Division Mitochondria are tubular, highly dynamic organelles that continuously fuse and divide in a regulated manner. A balance of fusion and division controls mitochondrial morphol- ogy; imbalanced dynamics leads to altered morphology, which is associated with a variety of pathological conditions. When fusion is decreased, mitochondria fragment into small, spherical mitochondria that are often characterized by swollen cristae and impaired respiratory functions. When division is inhibited, tubular mitochondria fuse, generating elongated mitochondrial tubules with increased connectivity. In some neurons, however, decreased division leads to enlarged, spherical mitochondria. Highlighting the importance of mitochondrial fusion and division in human health and disease, mutations in mitochondrial dynamics components have recently been linked to several neurodevelopmental and neurodegenerative diseases, including a birth defect with multiple neurological disorders (Drp1), Parkinson’s disease (Parkin and Pink1), autosomal dominant optic atrophy type 1 (Opa1), and Charcot-Marie-Tooth neuropathies (Mfn2 and GDAP1). In addition, although Alzheimer’s and Huntington’s diseases are not associated with such mutations, they do show altered activity and abundance of mitochondrial dynamics components. Core Machineries for Mitochondrial Fusion and Division Dynamin-related GTPases feature prominently in mitochondrial fusion and division. Complexes of mitofusin 1 and 2 (Fzo1) control outer-membrane fusion, whereas Opa1 (Mgm1) mediates inner-membrane fusion. In addition to its role in fusion, Opa1 (Mgm1) has been implicated in direct control of cristae junctions. For mitochondrial division, Drp1 (Dnm1) is recruited to the organelle surface, where it assembles into spiral filaments that are thought to generate mechanical force, constricting and pinching off the mitochondria. Regulation of Fusion Although outer- and inner-membrane fusion events are coordinated, these processes require separate machineries. In the outer membrane, levels of mitofusins (Fzo1), which are regulated by ubiquitin proteasome pathway, influence the amount of organelle fusion. In mammals, mitofusins are ubiquitinated by two E3 ligases, MITOL/March5 and Parkin. MITOL/March5 is located in the outer membrane and ubiquitinates mitofusin 1. Parkin is translocated to dysfunctional, depolarized mitochondria by the Pink1 kinase. Ubiquit- ination and proteasomal degradation of mitofusins inhibit refusion of damaged mitochondria and promote autophagic degradation of mitochondria. The ubiquitin proteasome pathway plays a similar role in yeast, with the ubiquitin ligase SCFMdm30 regulating the levels of Fzo1. Mitochondrial fusion can be modulated independently of the amount of fusion proteins. For instance, the proapoptotic Bcl-2 family members Bax and Bcl-xL stimulate mito- fusin 2 activity, whereas a mitofusin-binding protein (MIB) inhibits mitofusin 1 and 2. In the inner membrane, Opa1 (Mgm1) exists in two forms: l-Opa1 (l-Mgm1) is integral to the inner membrane, and s-Opa1 (s-Mgm1) is soluble as a result of proteolytic cleavage of the integrated membrane form. Both are required for mitochondrial fusion. In mammals, several inner membrane-localized proteases cleave Opa1, including PARL, i-AAA, m-AAA, and Oma1. In yeast, a homolog of PARL, Pcp1, cleaves Mgm1. Changes in matrix ATP levels and the membrane potential across the inner membrane affect Opa1 (Mgm1) processing. Because mitochondrial have two membranes, efficient fusion of the organelle requires coordination of outer- and inner-membrane fusion. Ugo1, an outer-membrane protein binds Fzo1 and Mgm1, linking these two fusion events in yeast. The mammalian homolog of Ugo1 remains unidentified. Regulation of Division Machinery Multiple integral outer-membrane proteins recruit Drp1 (Dnm1) to mitochondria. In mammals, Mff and MiD49/51 interact directly with Drp1, anchoring it to the mitochondrial sur- face. Fis1 was the first outer-membrane protein identified as a tether for Drp1, but its function has been challenged recently. One other integral outer-membrane protein, GDAP1, has also been implicated in Drp1-dependent mitochondrial division in mammals; however, the exact function of this protein awaits elucidation. Several types of posttranslational modifications regulate Drp1 in mammals. Similar to mitofusins, the activity of Drp1 appears to be regulated by MITOL/March5-dependent ubiquitination. In addition, SUMOylation, phosphorylation, and N-nitrosylation of Drp1 also control its functions. Although Drp1 appears to bind directly to outer-membrane receptors to promote division in mammalian cells, Dnm1 is tethered to the outer membrane by two functionally redundant protein complexes in yeast. Fis1 recruits Dnm1 via two WD40 domain-containing adaptor proteins, Mdv1 and Caf4. Parallel to this mechanism, Mdm36 and the corti- cal protein Num1 retain Dnm1 at the mitochondrial surface. The Num1-Mdm36 mechanism connects mitochondria to the cell cortex and promotes appropriate segregation and inheritance of mitochondria during cytokinesis. In algae, Dnm1 is proposed to associate with Fis1 and the WD40 domain-containing protein Mda1 on the outer membrane. Additionally, two proteins related to bacterial division components, FtsZ and ZED, are located on the matrix side of the inner membrane and form a ring structure, which potentially mediates inner-membrane division. The machinery necessary for inner-membrane division has yet to be identified in mammals and yeast. Abbreviations Mfn, mitofusin; G, GTPase; R, ring-domain; Ub, ubiquitin; P, phosphate; SUMO, small ubiquitin-like modifier; OM, outer membrane; IMS, intermembrane space; IM, inner mem- brane; SCF, Skp1-cullin-F box; MEF, mouse embryonic fibroblast. When the names for mammalian and their yeast orthologs differ, the yeast name is in parentheses. Acknowledgments We thank M. Iijima for helpful discussions and Y. Kageyama for providing the image of mitochondria in mouse embryonic fibroblasts. Y.T. is supported by a Japan Society for the Promotion of Science fellowship. H.S. is supported by a National Institutes of Health grant (GM89853). RefeRences Campello, S., and Scorrano, L. (2010). Mitochondrial shape changes: orchestrating cell pathophysiology. EMBO Rep. 11, 678–684. Chang, C.R., and Blackstone, C. (2010). Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann. N Y Acad. Sci. 1201, 34–39. Chen, H., and Chan, D.C. (2009). Mitochondrial dynamics—fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum. Mol. Genet. 18 (R2), R169–R176. Hoppins, S., and Nunnari, J. (2009). The molecular mechanism of mitochondrial fusion. Biochim. Biophys. Acta 1793, 20–26. Kageyama, Y., Zhang, Z., and Sesaki, H. (2011). Mitochondrial division: molecular machinery and physiological functions. Curr. Opin. Cell Biol. Kuroiwa, T. (2010). Mechanisms of organelle division and inheritance and their implications regarding the origin of eukaryotic cells. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 86, 455–471. McBride, H., and Soubannier, V. (2010). Mitochondrial function: OMA1 and OPA1, the grandmasters of mitochondrial health. Curr. Biol. 20, R274–R276. Palmer, C.S., Osellame, L.D., Laine, D., Koutsopoulos, O.S., Frazier, A.E., and Ryan, M.T. (2011). MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO Rep. 12, 565–573. Westermann, B. (2010). Mitochondrial dynamics in model organisms: what yeasts, worms and flies have taught us about fusion and fission of mitochondria. Semin. Cell Dev. Biol. 21, 542–549. Youle, R.J., and Narendra, D.P. (2011). Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14. 1158.e1 Cell 145, June 24, 2011 ©2011 Elsevier Inc. DOI 10.1016/j.cell.2011.06.018.
Recommended publications
  • Dissertation Philip Böhler

    Dissertation Philip Böhler

    Three Tales of Death: New Pathways in the Induction, Inhibition and Execution of Apoptosis Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Philip Böhler aus Bonn Düsseldorf, Juni 2019 aus dem Institut für Molekulare Medizin I der Heinrich-Heine-Universität Düsseldorf Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Berichterstatter: 1. Prof. Dr. Sebastian Wesselborg 2. Prof. Dr. Henrike Heise Tag der mündlichen Prüfung: 29. Oktober 2019 “Where the first primal cell was, there was I also. Where man is, there am I. When the last life crawls under freezing stars, there will I be.” — DEATH, in: Mort, by Terry Pratchett “Right away I found out something about biology: it was very easy to find a question that was very interesting, and that nobody knew the answer to.” — Richard Feynman, in: Surely You're Joking, Mr. Feynman! Acknowledgements (Danksagung) Acknowledgements (Danksagung) Viele Menschen haben zum Gelingen meiner Forschungsarbeit und dieser Dissertation beigetragen, und nicht alle können hier namentlich erwähnt werden. Dennoch möchte ich einige besonders hervorheben. An erster Stelle möchte ich Professor Sebastian Wesselborg danken, der diese Dissertation als Erstgutachter betreut hat und der mir die Möglichkeit gab, die dazugehörigen experimentellen Arbeiten am Institut für Molekulare Medizin durchzuführen. Er und Professor Björn Stork, dem ich für die herzliche Aufnahme in seine Arbeitsgruppe danke, legten durch die richtige Mischung aus aktiver Förderung und dem Freiraum zur Umsetzung eigener wissenschaftlicher Ideen die ideale Grundlage für die Forschungsprojekte, aus denen diese Dissertation entstand. Professorin Henrike Heise, die sich freundlicherweise zur Betreuung dieser Dissertation als Zweitgutachterin bereiterklärt hat, gilt ebenfalls mein herzlicher Dank.
  • Huang Grad.Sunysb 0771E 10211

    Huang Grad.Sunysb 0771E 10211

    SSStttooonnnyyy BBBrrrooooookkk UUUnnniiivvveeerrrsssiiitttyyy The official electronic file of this thesis or dissertation is maintained by the University Libraries on behalf of The Graduate School at Stony Brook University. ©©© AAAllllll RRRiiiggghhhtttsss RRReeessseeerrrvvveeeddd bbbyyy AAAuuuttthhhooorrr... Development of a quantitative assay for mitochondrial fusion and characterization of a lipid signaling pathway on the mitochondrial surface A Dissertation Presented by Huiyan Huang to The Graduate School in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Molecular and Cellular Pharmacology Stony Brook University August 2010 Stony Brook University The Graduate School Huiyan Huang We, the dissertation committee for the above candidate for the Doctor of Philosophy degree, hereby recommend acceptance of this dissertation. Michael A. Frohman, M.D., Ph.D. - Dissertation Advisor Professor Department of Pharmacological Sciences Daniel F. Bogenhagen, MD - Chairperson of the Defense Professor Department of Pharmacological Sciences Robert S. Haltiwanger, Ph.D. Professor Department of Biochemistry and Structural Biology Deborah A. Brown, Ph.D. Professor Department of Biochemistry and Structural Biology This dissertation is accepted by the Graduate School. Lawrence Martin Dean of the Graduate School ii Abstract of the Dissertation Development of a quantitative assay for mitochondrial fusion and characterization of a lipid signaling pathway on the mitochondrial surface by Huiyan Huang Doctor of Philosophy in Molecular and Cellular Pharmacology Stony Brook University 2010 Mitochondria continuously undergo fusion and fission, the relative rates of which define their morphology. Mitochondrial fusion is currently assayed by fusing together cells expressing GFP or RFP in their mitochondria and then scoring the frequency of cells with yellow mitochondria (representing fused green and red mitochondria).
  • MARCH5 Requires MTCH2 to Coordinate Proteasomal Turnover of the MCL1:NOXA Complex

    MARCH5 Requires MTCH2 to Coordinate Proteasomal Turnover of the MCL1:NOXA Complex

    Cell Death & Differentiation (2020) 27:2484–2499 https://doi.org/10.1038/s41418-020-0517-0 ARTICLE MARCH5 requires MTCH2 to coordinate proteasomal turnover of the MCL1:NOXA complex 1,2 1,2,5 1,2 1,2 1,2,3 1,2 Tirta Mario Djajawi ● Lei Liu ● Jia-nan Gong ● Allan Shuai Huang ● Ming-jie Luo ● Zhen Xu ● 4 1,2 1,2 1,2 Toru Okamoto ● Melissa J. Call ● David C. S. Huang ● Mark F. van Delft Received: 3 July 2019 / Revised: 6 February 2020 / Accepted: 7 February 2020 / Published online: 24 February 2020 © The Author(s) 2020. This article is published with open access Abstract MCL1, a BCL2 relative, is critical for the survival of many cells. Its turnover is often tightly controlled through both ubiquitin-dependent and -independent mechanisms of proteasomal degradation. Several cell stress signals, including DNA damage and cell cycle arrest, are known to elicit distinct E3 ligases to ubiquitinate and degrade MCL1. Another trigger that drives MCL1 degradation is engagement by NOXA, one of its BH3-only protein ligands, but the mechanism responsible has remained unclear. From an unbiased genome-wide CRISPR-Cas9 screen, we discovered that the ubiquitin E3 ligase MARCH5, the ubiquitin E2 conjugating enzyme UBE2K, and the mitochondrial outer membrane protein MTCH2 co- — fi 1234567890();,: 1234567890();,: operate to mark MCL1 for degradation by the proteasome speci cally when MCL1 is engaged by NOXA. This mechanism of degradation also required the MCL1 transmembrane domain and distinct MCL1 lysine residues to proceed, suggesting that the components likely act on the MCL1:NOXA complex by associating with it in a specific orientation within the mitochondrial outer membrane.
  • Mitochondrial Rhomboid PARL Regulates Cytochrome C Release During Apoptosis Via OPA1-Dependent Cristae Remodeling

    Mitochondrial Rhomboid PARL Regulates Cytochrome C Release During Apoptosis Via OPA1-Dependent Cristae Remodeling

    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Mitochondrial Rhomboid PARL Regulates Cytochrome c Release during Apoptosis via OPA1-Dependent Cristae Remodeling Sara Cipolat,1,7 Tomasz Rudka,2,7 Dieter Hartmann,2,7 Veronica Costa,1 Lutgarde Serneels,2 Katleen Craessaerts,2 Kristine Metzger,2 Christian Frezza,1 Wim Annaert,3 Luciano D’Adamio,5 Carmen Derks,2 Tim Dejaegere,2 Luca Pellegrini,6 Rudi D’Hooge,4 Luca Scorrano,1,* and Bart De Strooper2,* 1 Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy 2 Neuronal Cell Biology and Gene Transfer Laboratory 3 Membrane Trafficking Laboratory Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB4) and K.U.Leuven, Leuven, Belgium 4 Laboratory of Biological Psychology, K.U.Leuven, Leuven, Belgium 5 Albert Einstein College of Medicine, Bronx, NY 10461, USA 6 Centre de Recherche Robert Giffard, Universite` Laval, G1J 2G3 Quebec, Canada 7 These authors contribute equally to this work. *Contact: [email protected] (L.S.); [email protected] (B.D.S.) DOI 10.1016/j.cell.2006.06.021 SUMMARY been identified in D. melanogaster (Freeman, 2004), where they function as essential activators of the epidermal Rhomboids, evolutionarily conserved integral growth factor (EGF) signaling pathway, proteolytically membrane proteases, participate in crucial sig- cleaving the EGF receptor ligands Spitz, Gurken, and naling pathways. Presenilin-associated rhom- Keren. Since all Rhomboids share a conserved serine boid-like (PARL) is an inner mitochondrial protease catalytic dyad (Lemberg et al., 2005), it has membrane rhomboid of unknown function, been suggested that they are able to cleave proteins in whose yeast ortholog is involved in mito- the transmembrane domain.
  • PARL (Human) Recombinant Protein (P01)

    PARL (Human) Recombinant Protein (P01)

    Produktinformation Diagnostik & molekulare Diagnostik Laborgeräte & Service Zellkultur & Verbrauchsmaterial Forschungsprodukte & Biochemikalien Weitere Information auf den folgenden Seiten! See the following pages for more information! Lieferung & Zahlungsart Lieferung: frei Haus Bestellung auf Rechnung SZABO-SCANDIC Lieferung: € 10,- HandelsgmbH & Co KG Erstbestellung Vorauskassa Quellenstraße 110, A-1100 Wien T. +43(0)1 489 3961-0 Zuschläge F. +43(0)1 489 3961-7 [email protected] • Mindermengenzuschlag www.szabo-scandic.com • Trockeneiszuschlag • Gefahrgutzuschlag linkedin.com/company/szaboscandic • Expressversand facebook.com/szaboscandic PARL (Human) Recombinant Protein Gene Alias: PRO2207, PSARL, PSARL1, PSENIP2, (P01) RHBDS1 Gene Summary: This gene encodes a mitochondrial Catalog Number: H00055486-P01 integral membrane protein. Following proteolytic Regulation Status: For research use only (RUO) processing of this protein, a small peptide (P-beta) is formed and translocated to the nucleus. This gene may Product Description: Human PARL full-length ORF ( be involved in signal transduction via regulated NP_061092.3, 1 a.a. - 379 a.a.) recombinant protein with intramembrane proteolysis of membrane-tethered GST-tag at N-terminal. precursor proteins. Variation in this gene has been associated with increased risk for type 2 diabetes. Sequence: Alternative splicing results in multiple transcript variants MAWRGWAQRGWGCGQAWGASVGGRSCEELTAVLT encoding different isoforms. [provided by RefSeq] PPQLLGRRFNFFIQQKCGFRKAPRKVEPRRSDPGTSG EAYKRSALIPPVEETVFYPSPYPIRSLIKPLFFTVGFTGC
  • RING-Type E3 Ligases: Master Manipulators of E2 Ubiquitin-Conjugating Enzymes and Ubiquitination☆

    RING-Type E3 Ligases: Master Manipulators of E2 Ubiquitin-Conjugating Enzymes and Ubiquitination☆

    Biochimica et Biophysica Acta 1843 (2014) 47–60 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamcr Review RING-type E3 ligases: Master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination☆ Meredith B. Metzger a,1, Jonathan N. Pruneda b,1, Rachel E. Klevit b,⁎, Allan M. Weissman a,⁎⁎ a Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, 1050 Boyles Street, Frederick, MD 21702, USA b Department of Biochemistry, Box 357350, University of Washington, Seattle, WA 98195, USA article info abstract Article history: RING finger domain and RING finger-like ubiquitin ligases (E3s), such as U-box proteins, constitute the vast Received 5 March 2013 majority of known E3s. RING-type E3s function together with ubiquitin-conjugating enzymes (E2s) to medi- Received in revised form 23 May 2013 ate ubiquitination and are implicated in numerous cellular processes. In part because of their importance in Accepted 29 May 2013 human physiology and disease, these proteins and their cellular functions represent an intense area of study. Available online 6 June 2013 Here we review recent advances in RING-type E3 recognition of substrates, their cellular regulation, and their varied architecture. Additionally, recent structural insights into RING-type E3 function, with a focus on im- Keywords: RING finger portant interactions with E2s and ubiquitin, are reviewed. This article is part of a Special Issue entitled: U-box Ubiquitin–Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf. Ubiquitin ligase (E3) Published by Elsevier B.V. Ubiquitin-conjugating enzyme (E2) Protein degradation Catalysis 1.
  • Mitochondrial Network Fragmentation Modulates Mutant Mtdna Accumulation Independently of Absolute Fission-Fusion Rates

    Mitochondrial Network Fragmentation Modulates Mutant Mtdna Accumulation Independently of Absolute Fission-Fusion Rates

    bioRxiv preprint doi: https://doi.org/10.1101/409128; this version posted September 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Mitochondrial network fragmentation modulates mutant mtDNA accumulation independently of absolute fission-fusion rates Juvid Aryaman1, Charlotte Bowles2, Nick S. Jones1,3*, Iain G. Johnston2,3,4† 1 Department of Mathematics, Imperial College London, London, United Kingdom 2 School of Biosciences, University of Birmingham, Birmingham, United Kingdom 3 EPSRC Centre for the Mathematics of Precision Healthcare, Imperial College London, London, United Kingdom 4 Lead Contact *[email protected] †[email protected] Summary Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may also be associated with healthy aging. MtDNA is stochastically replicated and degraded, and exists within organelles which undergo dynamic fusion and fission. The role of the resulting mitochondrial networks in determining the time evolution of the cellular proportion of mutated mtDNA molecules (heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy variance), remains incompletely understood. Heteroplasmy variance is particularly important since it modulates the number of pathological cells in a tissue. Here, we provide the first wide- reaching mathematical treatment which bridges mitochondrial network and genetic states. We show that, for a range of models, the rate of increase in heteroplasmy variance, and the rate of de novo mutation, is proportionately modulated by the fraction of unfused mitochondria, independently of the absolute fission- fusion rate.
  • MARCH5-Dependent Degradation of MCL1/NOXA Complexes Defines

    MARCH5-Dependent Degradation of MCL1/NOXA Complexes Defines

    Cell Death & Differentiation (2020) 27:2297–2312 https://doi.org/10.1038/s41418-020-0503-6 ARTICLE MARCH5-dependent degradation of MCL1/NOXA complexes defines susceptibility to antimitotic drug treatment 1 1 1 2 2 1,3,4 Manuel D. Haschka ● Gerlinde Karbon ● Claudia Soratroi ● Katelyn L. O’Neill ● Xu Luo ● Andreas Villunger Received: 7 August 2019 / Revised: 17 January 2020 / Accepted: 21 January 2020 / Published online: 3 February 2020 © The Author(s) 2020. This article is published with open access Abstract Cells experiencing delays in mitotic progression are prone to undergo apoptosis unless they can exit mitosis before proapoptotic factors reach a critical threshold. Microtubule targeting agents (MTAs) arrest cells in mitosis and induce apoptotic cell death engaging the BCL2 network. Degradation of the antiapoptotic BCL2 family member MCL-1 is considered to set the time until onset of apoptosis upon MTA treatment. MCL1 degradation involves its interaction with one of its key binding partners, the proapoptotic BH3-only protein NOXA. Here, we report that the mitochondria-associated E3- ligase MARCH5, best known for its role in mitochondrial quality control and regulation of components of the mitochondrial fission machinery, controls the levels of MCL1/NOXA protein complexes in steady state as well as during mitotic arrest. 1234567890();,: 1234567890();,: Inhibition of MARCH5 function sensitizes cancer cells to the proapoptotic effects of MTAs by the accumulation of NOXA and primes cancer cells that may undergo slippage to escape death in mitosis to cell death in the next G1 phase. We propose that inhibition of MARCH5 may be a suitable strategy to sensitize cancer cells to antimitotic drug treatment.
  • PINK1 and Parkin Mitochondrial Quality Control: a Source of Regional Vulnerability in Parkinson’S Disease Preston Ge1,2,3,4,5,6, Valina L

    PINK1 and Parkin Mitochondrial Quality Control: a Source of Regional Vulnerability in Parkinson’S Disease Preston Ge1,2,3,4,5,6, Valina L

    Ge et al. Molecular Neurodegeneration (2020) 15:20 https://doi.org/10.1186/s13024-020-00367-7 REVIEW Open Access PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson’s disease Preston Ge1,2,3,4,5,6, Valina L. Dawson1,2,3* and Ted M. Dawson1,2,3* Abstract That certain cell types in the central nervous system are more likely to undergo neurodegeneration in Parkinson’s disease is a widely appreciated but poorly understood phenomenon. Many vulnerable subpopulations, including dopamine neurons in the substantia nigra pars compacta, have a shared phenotype of large, widely distributed axonal networks, dense synaptic connections, and high basal levels of neural activity. These features come at substantial bioenergetic cost, suggesting that these neurons experience a high degree of mitochondrial stress. In such a context, mechanisms of mitochondrial quality control play an especially important role in maintaining neuronal survival. In this review, we focus on understanding the unique challenges faced by the mitochondria in neurons vulnerable to neurodegeneration in Parkinson’s and summarize evidence that mitochondrial dysfunction contributes to disease pathogenesis and to cell death in these subpopulations. We then review mechanisms of mitochondrial quality control mediated by activation of PINK1 and Parkin, two genes that carry mutations associated with autosomal recessive Parkinson’s disease. We conclude by pinpointing critical gaps in our knowledge of PINK1 and Parkin function, and propose that understanding the connection between the mechanisms of sporadic Parkinson’sand defects in mitochondrial quality control will lead us to greater insights into the question of selective vulnerability. Keywords: Parkinson disease, Parkin, PINK1, Mitochondria, Mitophagy, Selective vulnerability, Substantia nigra Background symptoms, and that the selective SNpc DA neuron toxin Parkinson’s disease (PD) is a late-onset neurodegenerative MPTP recapitulates the clinical phenotype of PD [2].
  • Genetic Correction of HAX1 in Induced Pluripotent Stem Cells from a Patient with Severe Congenital Neutropenia Improves Defective Granulopoiesis

    Genetic Correction of HAX1 in Induced Pluripotent Stem Cells from a Patient with Severe Congenital Neutropenia Improves Defective Granulopoiesis

    Bone Marrow Failure Syndromes ARTICLES Genetic correction of HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis Tatsuya Morishima,1 Ken-ichiro Watanabe,1 Akira Niwa,2 Hideyo Hirai,3 Satoshi Saida,1 Takayuki Tanaka,2 Itaru Kato,1 Katsutsugu Umeda,1 Hidefumi Hiramatsu,1 Megumu K. Saito,2 Kousaku Matsubara,4 Souichi Adachi,5 Masao Kobayashi,6 Tatsutoshi Nakahata,2 and Toshio Heike1 1Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto; 2Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto; 3Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto; 4Department of Pediatrics, Nishi-Kobe Medical Center, Kobe; 5Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto; and 6Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan ABSTRACT HAX1 was identified as the gene responsible for the autosomal recessive type of severe congenital neutropenia. However, the connection between mutations in the HAX1 gene and defective granulopoiesis in this disease has remained unclear, mainly due to the lack of a useful experimental model for this disease. In this study, we generated induced pluripotent stem cell lines from a patient presenting for severe congenital neutropenia with HAX1 gene deficiency, and analyzed their in vitro neutrophil differentiation potential by using a novel serum- and feeder-free directed differentiation culture system. Cytostaining and flow cytometric analyses of myeloid cells differentiated from patient-derived induced pluripotent stem cells showed arrest at the myeloid progenitor stage and apoptotic predisposition, both of which replicated abnormal granulopoiesis. Moreover, lentiviral transduction of the HAX1 cDNA into patient-derived induced pluripotent stem cells reversed disease-related abnormal granulopoiesis.
  • Human CLPB) Is a Potent Mitochondrial Protein Disaggregase That Is Inactivated By

    Human CLPB) Is a Potent Mitochondrial Protein Disaggregase That Is Inactivated By

    bioRxiv preprint doi: https://doi.org/10.1101/2020.01.17.911016; this version posted January 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Skd3 (human CLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations Ryan R. Cupo1,2 and James Shorter1,2* 1Department of Biochemistry and Biophysics, 2Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, U.S.A. *Correspondence: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.01.17.911016; this version posted January 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT Cells have evolved specialized protein disaggregases to reverse toxic protein aggregation and restore protein functionality. In nonmetazoan eukaryotes, the AAA+ disaggregase Hsp78 resolubilizes and reactivates proteins in mitochondria. Curiously, metazoa lack Hsp78. Hence, whether metazoan mitochondria reactivate aggregated proteins is unknown. Here, we establish that a mitochondrial AAA+ protein, Skd3 (human CLPB), couples ATP hydrolysis to protein disaggregation and reactivation. The Skd3 ankyrin-repeat domain combines with conserved AAA+ elements to enable stand-alone disaggregase activity. A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity. Indeed, PARL-activated Skd3 dissolves α-synuclein fibrils connected to Parkinson’s disease. Human cells lacking Skd3 exhibit reduced solubility of various mitochondrial proteins, including anti-apoptotic Hax1.
  • The Incomplete Puzzle of the BCL2 Proteins

    The Incomplete Puzzle of the BCL2 Proteins

    cells Perspective The Incomplete Puzzle of the BCL2 Proteins Hector Flores-Romero and Ana J. García-Sáez * Interfaculty Institute of Biochemistry, Eberhard-Karls-Universität Tübingen, 72076 Tübingen, Germany; [email protected] * Correspondence: [email protected] Received: 3 September 2019; Accepted: 26 September 2019; Published: 29 September 2019 Abstract: The proteins of the BCL2 family are key players in multiple cellular processes, chief amongst them being the regulation of mitochondrial integrity and apoptotic cell death. These proteins establish an intricate interaction network that expands both the cytosol and the surface of organelles to dictate the cell fate. The complexity and unpredictability of the BCL2 interactome resides in the large number of family members and of interaction surfaces, as well as on their different behaviours in solution and in the membrane. Although our current structural knowledge of the BCL2 proteins has been proven therapeutically relevant, the precise structure of membrane-bound complexes and the regulatory effect that membrane lipids exert over these proteins remain key questions in the field. Here, we discuss the complexity of BCL2 interactome, the new insights, and the black matter in the field. Keywords: BCL2 proteins; MOMP; protein membrane interactions; apoptosis; cancer therapy Perspective in BCL2 Universe The proteins of the BCL2 family are the main regulators of the intrinsic apoptotic pathway and constitute a fundamental part of tumorigenic cell dismissal and cancer treatment effectiveness [1,2]. Apoptosis effectors, or BAX-type proteins, are the most effective removers of damaged cells, while their antiapoptotic counterparts, or BCL2-type proteins, inhibit apoptotic cell death and play a role in chemotherapeutic resistance [3,4].