DOCSLIB.ORG

Mitochondrial Fusion and Fission in Mammals

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mitochondrial Fusion and Fission in Mammals ANRV288-CB22-04 ARI 28 September 2006 21:42 Mitochondrial Fusion and Fission in Mammals David C. Chan Division of Biology, California Institute of Technology, Pasadena, California; email: [email protected] Annu. Rev. Cell Dev. Biol. 2006. 22:79–99 Key Words First published online as a Review in mitochondrial dynamics, organelle morphology, membrane fusion, Advance on May 11, 2006 membrane trafficking The Annual Review of Cell and Developmental Biology is online at Abstract http://cellbio.annualreviews.org Eukaryotic cells maintain the overall shape of their mitochondria by This article’s doi: balancing the opposing processes of mitochondrial fusion and fission. by CALIFORNIA INSTITUTE OF TECHNOLOGY on 12/15/06. For personal use only. 10.1146/annurev.cellbio.22.010305.104638 Annu. Rev. Cell Dev. Biol. 2006.22:79-99. Downloaded from arjournals.annualreviews.org Unbalanced fission leads to mitochondrial fragmentation, and un- Copyright c 2006 by Annual Reviews. balanced fusion leads to mitochondrial elongation. Moreover, these All rights reserved processes control not only the shape but also the function of mito- 1081-0706/06/1110-0079$20.00 chondria. Mitochondrial dynamics allows mitochondria to interact with each other; without such dynamics, the mitochondrial popula- tion consists of autonomous organelles that have impaired function. Key components of the mitochondrial fusion and fission machinery have been identified, allowing initial dissection of their mechanisms of action. These components play important roles in mitochondrial function and development as well as programmed cell death. Dis- ruption of the fusion machinery leads to neurodegenerative disease. 79 ANRV288-CB22-04 ARI 28 September 2006 21:42 in mammals, although work in other systems Contents is discussed when relevant. INTRODUCTION................. 80 THE FUSION MACHINERY ...... 80 THE FUSION MACHINERY Mitofusins: Mfn1 and Mfn2 ....... 81 In mammalian cells, mitochondria take on a OPA1............................ 81 wide variety of shapes, ranging from long, THE FISSION MACHINERY ...... 83 interconnected tubules to individual, small Dynamin-Related Protein 1 ....... 83 spheres (Bereiter-Hahn & Voth 1994). In cul- Fis1. ............................. 83 tured fibroblasts, the mitochondrial popula- OTHER PLAYERS ................. 83 tion consists mostly of short and long tubules, MOLECULAR MECHANISM ..... 85 which constantly migrate along their long Fusion Mechanism ............... 85 axes along microtubule tracks (Chen & Chan Fission Mechanism ............... 87 2004). These migrations are saltatory, consist- BIOLOGICAL SIGNIFICANCE . 88 ing of movements back and forth along the Cell Biology of Fusion and Fission 88 tracks. In some cell types, the actin cytoskele- Mitochondrial Dynamics in ton is also used for transport (Hollenbeck & Development and Apoptosis . 89 Saxton 2005). While migrating along these Mitochondrial Dynamics in tracks, a pair of mitochondria can encounter Disease ....................... 91 each other end to end and fuse. Even though PERSPECTIVES ................... 92 an organized cytoskeleton is important as a scaffold for organizing the distribution and movement of mitochondria, it is not necessary for maintaining the tubular shape or fusion of mitochondria (Mattenberger et al. 2003). INTRODUCTION In molecular genetic studies, an initial In the past several years, there have been molecular inroad into a biological pathway tremendous advances in our understanding can greatly accelerate the identification of of the molecular basis of mitochondrial dy- additional genes. In the case of mitochon- namics. It is now well established that mi- drial dynamics, it was the identification of the tochondria are highly dynamic organelles Drosophila mitofusin gene, Fzo, in sperm mi- whose morphology, distribution, and activ- tochondrial fusion (Hales & Fuller 1997) that ity can be regulated by fusion and fission. drove rapid advances in our knowledge of the Several components of the core fusion and molecular basis of mitochondrial fusion and fission machinery have been identified, and fission. The yeast mitofusin homolog, Fzo1, experimental systems have been developed was found to function similarly in mitochon- by CALIFORNIA INSTITUTE OF TECHNOLOGY on 12/15/06. For personal use only. Annu. Rev. Cell Dev. Biol. 2006.22:79-99. Downloaded from arjournals.annualreviews.org to understand their molecular mechanism of drial fusion (Hermann et al. 1998, Rapaport action. et al. 1998), and genetic screens for extra- In addition to this molecular understand- genic suppressors of fusion mutants led to ing, genetic studies have revealed the impor- the identification of key molecules involved tance of these processes in normal cell func- in mitochondrial fission (Fekkes et al. 2000, tion, mammalian development, and human Mozdy et al. 2000, Tieu & Nunnari 2000). disease. Mitochondrial fusion is necessary for Details of yeast mitochondrial dynamics can normal respiratory function in cells, and per- be found in other excellent reviews (Meeusen turbations in fusion lead to developmental de- & Nunnari 2005, Okamoto & Shaw 2005, fects in mice and neurodegenerative disease in Shaw & Nunnari 2002). Much of the fusion humans. This review emphasizes advances in and fission machinery is conserved in mam- our understanding of mitochondrial dynamics mals (Chen & Chan 2004). 80 Chan ANRV288-CB22-04 ARI 28 September 2006 21:42 Mitofusins: Mfn1 and Mfn2 Mitofusins are conserved, large GTPases lo- calized to the mitochondrial outer membrane (Chen et al. 2003, Rojo et al. 2002, Santel & Fuller 2001). In mammals, there are two closely related mitofusin homologs, Mfn1 and Mfn2. Their essential role in mitochondrial fusion has been established through the gen- Figure 1 eration of mice with targeted mutations (Chen The mammalian mitochondrial fusion machinery. Schematic of Mfn1, et al. 2003). Cells lacking Mfn1 or Mfn2 have Mfn2, and OPA1. All three proteins contain GTPase domains and greatly reduced levels of mitochondrial fusion hydrophobic heptad repeat (HR) regions. The transmembrane (TM) (Chen et al. 2005, Chen et al. 2003). Because segments of the mitofusins are unusually long and contain charged residues of ongoing mitochondrial fission, the mito- that are thought to allow a U-turn in the mitochondrial outer membrane, chondrial population in mutant cells is highly so that almost the entire protein faces the cytosol (see Figure 2). fragmented. In the absence of both Mfn1 and The membrane topology of mitofusins Mfn2, there is absolutely no mitochondrial fu- makes them good candidates for molecules in- sion, resulting in complete loss of mitochon- volved in outer membrane fusion (Figure 1 drial tubules and poor mitochondrial function and 2). Both the N- and C-terminal regions (Chen et al. 2005). of these proteins protrude from the mitochon- Mfn1 and Mfn2 appear to play similar roles drial outer membrane into the cytosol (Rojo in mitochondrial fusion. Both molecules are et al. 2002). This topology implies a U-shaped necessary for normal levels of mitochondrial transmembrane domain, and consistent with fusion, but in cultured fibroblasts Mfn1 plays this, the transmembrane domain is unusu- a more active role (Chen et al. 2005). Fibrob- ally long and interrupted by several charged lasts lacking Mfn1 have more severely frag- residues. The N-terminal domain of mito- mented mitochondria and show less residual fusins contains a GTPase domain followed mitochondrial fusion than do those lacking by a hydrophobic heptad repeat region, HR1. Mfn2. Mfn1 and Mfn2 can functionally re- The C-terminal region contains a second hy- place each other. Cells lacking Mfn1 can drophobic heptad repeat region, HR2. As dis- be rescued by overexpression of Mfn2; con- cussed below, the HR1 and HR2 regions likely versely, cells lacking Mfn2 can be rescued by play important roles in the fusion reaction. overexpression of Mfn1. Moreover, Mfn-null cells can be fully rescued by overexpression of either mitofusin. These results clearly in- OPA1 dicate that the mitofusin homologs have very Mammalian OPA1 was initially identified as by CALIFORNIA INSTITUTE OF TECHNOLOGY on 12/15/06. For personal use only. similar biochemical activities. It is likely that Annu. Rev. Cell Dev. Biol. 2006.22:79-99. Downloaded from arjournals.annualreviews.org the gene mutated in autosomal dominant op- the cell-type-specific dependence for either tic atrophy (DOA), a common cause of in- Hydrophobic Mfn1 or Mfn2, such as the requirement for herited visual loss (Alexander et al. 2000, heptad repeat Mfn2 in the placenta (Chen et al. 2003), is a (HR): protein motif Delettre et al. 2000). OPA1 and the yeast ho- consequence of their relative expression levels consisting of a molog Mgm1 are dynamin family GTPases in different tissues. In spite of the functional seven-residue repeat, that are located within the mitochondrial in- designated ,in similarities of Mfn1 and Mfn2, some differ- abcdefg termembrane space and are associated with which the a and d ences in these molecules have been detected. the inner membrane (Griparic et al. 2004, residues are OPA1 function shows a dependence on Mfn1 primarily Herlan et al. 2003, Olichon et al. 2002, Satoh but not on Mfn2 (Cipolat et al. 2004), and hydrophobic et al. 2003, Wong et al. 2000) (Figures 1 and Mfn1 shows more activity in a mitochondrial DOA: dominant 2). The OPA1 gene produces multiple pro- tethering assay (Ishihara et al. 2004). optic atrophy tein isoforms, owing to extensive alternative www.annualreviews.org
Load more

Recommended publications
  • 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.
    [Show full text]
  • 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).
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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].
    [Show full text]
  • Mitochondrial Dynamic Abnormalities in Alzheimer's Disease Sirui Jiang Case Western Reserve University
    MITOCHONDRIAL DYNAMIC ABNORMALITIES IN ALZHEIMER’S DISEASE by SIRUI JIANG Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Dissertation Advisor: Dr. Xiongwei Zhu Department of Pathology CASE WESTERN RESERVE UNIVERSITY January 2019 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of SIRUI JIANG Candidate for the degree of Doctor of Philosophy* Dr. Shu Chen (Committee Chair) Dr. Xiongwei Zhu Dr. Xinglong Wang Dr. George Dubyak Dr. Charles Hoppel August 15, 2018 *We also certify that written approval has been obtained for any proprietary material contained therein Table of Contents Table of Contents 1 List of Figures 3 Acknowledgements 5 List of Abbreviations 7 Abstract 10 Chapter 1. Introduction 12 Introduction to Alzheimer’s Disease 13 General Information 13 Pathology 14 Pathogenesis 15 Introduction to Mitochondrial Dynamics 20 Mitochondrial Function and Neuronal Health 20 Mitochondrial Dynamics 21 Mitochondrial Dynamics and Mitochondrial Function 23 Mitochondrial Dynamics and Mitochondrial Transport 24 Mitochondrial Deficits in AD 26 Mitochondrial Dysfunction in AD 26 Aβ and Mitochondrial Dysfunction 27 Mitochondrial Dynamic Abnormalities in AD: Recent Advances 28 Conclusion 34 1 Chapter 2. Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex 36 Abstract 37 Background 39 Methods 43 Results 47 Discussion 54 Figures 60 Chapter 3. DLP1 Cleavage by Calpain in Alzheimer’s Disease 71 Abstract 72 Background 73 Methods 77 Results 80 Discussion 85 Figures 89 Chapter 4. Summary, Discussion and Future Directions 96 References 108 2 List of Figures Figure 2.1 Cre-mediated ablation of Mfn2 expression in the hippocampus and cortex of Mfn2 cKO mice 60 Figure 2.2 Quantification of DLP1 and OPA1 in cKO mice 61 Figure 2.3 Mfn2 ablation caused mitochondrial fragmentation and ultrastructural damage in the hippocampus in vivo as evidenced by electron microscopic analysis.
    [Show full text]
  • Phosphorylation and Cleavage of Presenilin-Associated Rhomboid-Like Protein (PARL) Promotes Changes in Mitochondrial Morphology
    Phosphorylation and cleavage of presenilin-associated rhomboid-like protein (PARL) promotes changes in mitochondrial morphology Danny V. Jeyaraju*, Liqun Xu†, Marie-Claude Letellier*, Sirisha Bandaru*, Rodolfo Zunino†, Eric A. Berg‡, Heidi M. McBride†§, and Luca Pellegrini*§ *Centre de Recherche Universite´Laval Robert-Giffard, 2601 ch. de la Canardie`re, Quebec City, QC, Canada G1J 2G3; †University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, Canada K1Y 4W7; and ‡21st Century Biochemicals, 33 Locke Drive, Marlboro, MA 01752-1146 Edited by Walter Neupert, Institute fu¨r Physiologische Chemie, Munich, Germany, and accepted by the Editorial Board October 12, 2006 (received for review June 14, 2006) Remodeling of mitochondria is a dynamic process coordinated by residues would be expected to survive the Ϸ100 million years of fusion and fission of the inner and outer membranes of the organelle, evolution separating mammalian orders (12, 13). This analysis mediated by a set of conserved proteins. In metazoans, the molecular suggests that emergence of the P␤ domain at the outset of verte- mechanism behind mitochondrial morphology has been recruited to brate evolution may be associated with the appearance of a new govern novel functions, such as development, calcium signaling, and mechanism of regulation of PARL. We have recently shown that apoptosis, which suggests that novel mechanisms should exist to this part of the PARL molecule undergoes two consecutive cleav- regulate the conserved membrane fusion/fission machinery. Here we age events, termed ␣ and ␤. The proximal ␣-cleavage is a consti- ␤ show that phosphorylation and cleavage of the vertebrate-specific P tutive processing associated with the protein import in the mito- domain of the mammalian presenilin-associated rhomboid-like chondria, whereas the distal ␤-cleavage is regulated through a (PARL) protease can influence mitochondrial morphology.
    [Show full text]
  • Mitochondrial Dynamics and Apoptosis
    Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Mitochondrial dynamics and apoptosis Der-Fen Suen, Kristi L. Norris, and Richard J. Youle1 Biochemistry Section, Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892, USA In healthy cells, mitochondria continually divide and 1, whereas others, such as Bax and Bak, activate apopto- fuse to form a dynamic interconnecting network. The sis. Bax and Bak actively induce cytochrome c release molecular machinery that mediates this organelle fis- from mitochondria within cells and in cell-free systems, sion and fusion is necessary to maintain mitochondrial both of which are inhibited by anti-apoptotic Bcl-2 fam- integrity, perhaps by facilitating DNA or protein quality ily members. As the anti-apoptotic Bcl-2 family mem- control. This network disintegrates during apoptosis at bers closely resemble the proapoptotic members in the time of cytochrome c release and prior to caspase structure, they may function as dominant negative in- activation, yielding more numerous and smaller mito- hibitors by binding and inhibiting Bax and Bak. Another chondria. Recent work shows that proteins involved in class of disparate proteins including Puma and Bim, mitochondrial fission and fusion also actively participate called BH3-only proteins, shares a short motif with Bcl-2 in apoptosis induction. This review will cover the recent family proteins and regulates their activity. One model advances and presents competing models on how the posits that upon apoptosis initiation, BH3-only proteins mitochondrial fission and fusion machinery may inter- are induced and then bind and inhibit anti-apoptotic sect apoptosis pathways.
    [Show full text]
  • Mitochondrial Fusion: the Machineries in and Out
    Trends in Cell Biology OPEN ACCESS Review Mitochondrial Fusion: The Machineries In and Out Song Gao 1,2,* and Junjie Hu 3,* Mitochondria are highly dynamic organelles that constantly undergo fission and Highlights fusion. Disruption of mitochondrial dynamics undermines their function and Crystal structures of truncated mitofusin causes several human diseases. The fusion of the outer (OMM) and inner mito- (MFN)1 and MFN2, the dynamin-like chondrial membranes (IMM) is mediated by two classes of dynamin-like protein fusogens of the outer mitochondrial membrane, reveal their structural kinship (DLP): mitofusin (MFN)/fuzzy onions 1 (Fzo1) and optic atrophy 1/mitochondria to bacterial dynamin-like protein (BDLP). genome maintenance 1 (OPA1/Mgm1). Given the lack of structural information Human MFN1 and MFN2 bear subtle on these fusogens, the molecular mechanisms underlying mitochondrial fusion differences that govern the distinct bio- remain unclear, even after 20 years. Here, we review recent advances in struc- chemical properties. tural studies of the mitochondrial fusion machinery, discuss their implication GTP-dependent dimerization and con- for DLPs, and summarize the pathogenic mechanisms of disease-causing muta- formational changes are key features of tions in mitochondrial fusion DLPs. MFNs in driving outer membrane fusion. Short optic atrophy 1/short mitochon- The Mitochondrial Fusion Machinery dria genome maintenance 1 (s-OPA1/ Mitochondria are double-membrane organelles that confer various essential cellular functions, s-Mgm1) resembles fission dynamins including energy production, metabolism, apoptosis, and innate immunity [1]. They form a highly in 3D architecture, highlighting a mech- anism of inner mitochondrial membrane fi dynamic network and constantly undergo cycles of fusion and ssion.
    [Show full text]
  • Mitochondrial Membrane Proteins and VPS35 Orchestrate Selective Removal of Mtdna
    bioRxiv preprint doi: https://doi.org/10.1101/2021.08.06.455397; this version posted August 6, 2021. 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. 1 Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA. 2 David Pla-Martin1,2*, Ayesha Sen1, Sebastian Kallabis2, Julian Nüchel3, Kanjanamas Maliphol1, 3 Julia Hofmann1, Marcus Krüger2 and Rudolf J. Wiesner1,2,4 4 5 Affiliations 6 1Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of 7 Köln, Köln, Germany 8 2Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases 9 (CECAD), University of Köln, Köln, Germany 10 3Center for Biochemistry, Faculty of Medicine, University of Köln, Köln, Germany 11 4Center for Molecular Medicine Cologne, University of Köln, Köln, Germany 12 * Corresponding author: David Pla-Martin, PhD; [email protected] 13 Abstract 14 Integrity of mitochondrial DNA (mtDNA), encoding several subunits of the respiratory chain, is 15 essential to maintain mitochondrial fitness. Mitochondria, as a central hub for metabolism, are 16 affected in a wide variety of human diseases but also during normal ageing, where mtDNA 17 integrity is compromised. Mitochondrial quality control mechanisms work at different levels, and 18 mitophagy and its variants are critical to remove dysfunctional mitochondria together with 19 mtDNA to maintain cellular homeostasis. Understanding the mechanisms governing a selective 20 turnover of mutation-bearing mtDNA without affecting the entire mitochondrial pool is 21 fundamental to design therapeutic strategies against mtDNA diseases and ageing. Here we 22 show that mtDNA depletion after expressing a dominant negative version of the mitochondrial 23 helicase Twinkle, or by chemical means, is due to an exacerbated mtDNA turnover.
    [Show full text]
  • Mitochondrial Fusion Exploits a Therapeutic Vulnerability of Pancreatic Cancer
    Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer Meifang Yu, … , Anirban Maitra, Cullen M. Taniguchi JCI Insight. 2019. https://doi.org/10.1172/jci.insight.126915. Research In-Press Preview Gastroenterology Oncology Graphical abstract Find the latest version: https://jci.me/126915/pdf Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer Meifang Yu1, Nicholas D. Nguyen1, Yanqing Huang1, Daniel Lin1, Tara N. Fujimoto1, Jessica M. Molkentine2, Amit Deorukhkar3, Ya’an Kang3, F. Anthony San Lucas4, Conrad J. Fernandes1, Eugene J. Koay5, Sonal Gupta6, 7, Haoqiang Ying8, Albert C. Koong5, Joseph M. Herman5, Jason B. Fleming9, Anirban Maitra6, 7, Cullen M. Taniguchi1,5†* Short title: Modulating mitochondrial dynamics to inhibit PDAC Brief Summary: Mitochondrial fusion in pancreatic cancer cells induces mitophagy, Which alters tumor energetics and correlates With improved survival in mouse models. Affiliations: 1 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2 Department of Radiation Oncology, University of Pittsburgh, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA. 3 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 4 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 5 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 6 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 7 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 8 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
    [Show full text]
  • A Small Natural Molecule Promotes Mitochondrial Fusion Through Inhibition of the Deubiquitinase USP30
    npg Inhibition of USP30 induces mitochondrial fusion Cell Research (2014) 24:482-496. 482 © 2014 IBCB, SIBS, CAS All rights reserved 1001-0602/14 $ 32.00 npg ORIGINAL ARTICLE www.nature.com/cr A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30 Wen Yue1, 2, *, Ziheng Chen1, 2, *, Haiyang Liu3, Chen Yan3, Ming Chen1, 2, Du Feng4, Chaojun Yan6, Hao Wu1, 2, Lei Du1, 2, Yueying Wang1, 2, Jinhua Liu4, Xiaohu Huang5, Laixin Xia1, Lei Liu1, Xiaohui Wang1, Haijing Jin1, Jun Wang1, Zhiyin Song6, Xiaojiang Hao3, Quan Chen1, 2, 4 1Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; 2University of Chinese Academy of Sciences, Beijing 100049, China; 3The State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650204, China; 4College of Life Sciences, Nankai University, Tianjin 300071, China; 5State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; 6 College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China Mitochondrial fusion is a highly coordinated process that mixes and unifies the mitochondrial compartment for normal mitochondrial functions and mitochondrial DNA inheritance. Dysregulated mitochondrial fusion causes mitochondrial fragmentation, abnormal mitochondrial physiology and inheritance, and has been causally linked with a number of neuronal diseases. Here, we identified a diterpenoid derivative 15-oxospiramilactone (S3) that potently induced mitochondrial fusion to restore the mitochondrial network and oxidative respiration in cells that are deficient in either Mfn1 or Mfn2.
    [Show full text]