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Mitochondria on Guard: Role of Mitochondrial Fusion and Fission in the Regulation of Apoptosis

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Book cover BCL-2 Protein Family

Part of the book series: Advances in Experimental Medicine and Biology ((volume 687))

Abstract

Mitochondria are highly dynamic organelles that constantly change shape and structure in response to different stimuli and metabolic demands of the cell. Mitochondrial structure in the cell is predominantly regulated by cycles of fusion and fission. These two processes are tightly regulated and under physiological conditions, mitochondrial fusion is evenly counterbalanced by fission. During apoptosis, mitochondria undergo extensive fragmentation, which precedes caspase activation, whereas inhibition of the mitochondrial fission machinery blocks or delays cell death. Aberrant mitochondrial fusion and fission have also emerged as important mechanisms in the development of disease.

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References

  1. Malka F, Guillery O, Cifuentes-Diaz C et al. Separate fusion of outer and inner mitochondrial membranes. EMBO Rep 2005; 6:853–859.

    Article  CAS  PubMed  Google Scholar 

  2. Meeusen S, McCaffery JM, Nunnari J. Mitochondrial fusion intermediates revealed in vitro. Science 2004; 305:1747–1752.

    Article  CAS  PubMed  Google Scholar 

  3. Chen H, Detmer SA, Ewald AJ et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 2003; 160:189–200.

    Article  CAS  PubMed  Google Scholar 

  4. Ishihara N, Eura Y, Mihara K. Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J Cell Sci 2004; 117:6535–6546.

    Article  CAS  PubMed  Google Scholar 

  5. Koshiba T, Detmer SA, Kaiser JT et al. Structural basis of mitochondrial tethering by mitofusin complexes. Science 2004; 305:858–862.

    Article  CAS  PubMed  Google Scholar 

  6. Neuspiel M, Zunino R, Gangaraju S et al. Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation and reduces susceptibility to radical induced depolarization. J Biol Chem 2005; 280:25060–25070.

    Article  CAS  PubMed  Google Scholar 

  7. Karbowski M, Arnoult D, Chen H et al. Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. J Cell Biol 2004; 164:493–499.

    Article  CAS  PubMed  Google Scholar 

  8. Delettre C, Lenaers G, Griffoin JM et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 2000; 26:207–210.

    Article  CAS  PubMed  Google Scholar 

  9. Olichon A, Baricault L, Gas N et al. Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 2003; 278:7743–7746.

    Article  CAS  PubMed  Google Scholar 

  10. Detmer SA, Chan DC. Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 2007; 8:870–879.

    Article  CAS  PubMed  Google Scholar 

  11. Guillery O, Malka F, Landes T et al. Metalloprotease-mediated OPA1 processing is modulated by the mitochondrial membrane potential. Biol Cell 2008; 100:315–325.

    Article  CAS  PubMed  Google Scholar 

  12. Eura Y, Ishihara N, Oka T et al. Identification of a novel protein that regulates mitochondrial fusion by modulating mitofusin (Mfn) protein function. J Cell Sci 2006; 119:4913–4925.

    Article  CAS  PubMed  Google Scholar 

  13. Choi SY, Huang P, Jenkins GM et al. A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis. Nat Cell Biol 2006; 8:1255–1262.

    Article  CAS  PubMed  Google Scholar 

  14. Hajek P, Chomyn A, Attardi G. Identification of a novel mitochondrial complex containing mitofusin 2 and stomatin-like protein 2. J Biol Chem 2007; 282:5670–5681.

    Article  CAS  PubMed  Google Scholar 

  15. Da Cruz S, Parone PA, Gonzalo P et al. SLP-2 interacts with prohibitins in the mitochondrial inner membrane and contributes to their stability. Biochim Biophys Acta 2008; 1783:904–911.

    PubMed  Google Scholar 

  16. Cipolat S, Rudka T, Hartmann D et al. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 2006; 126:163–175.

    Article  CAS  PubMed  Google Scholar 

  17. Griparic L, Kanazawa T, van der Bliek AM. Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol 2007; 178:757–764.

    Article  CAS  PubMed  Google Scholar 

  18. Song Z, Chen H, Fiket M et al. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential and Yme1L. J Cell Biol 2007; 178:749–755.

    Article  CAS  PubMed  Google Scholar 

  19. Ishihara N, Fujita Y, Oka T et al. Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J 2006; 25:2966–2977.

    Article  CAS  PubMed  Google Scholar 

  20. Duvezin-Caubet S, Koppen M, Wagener J et al. OPA1 processing reconstituted in yeast depends on the subunit composition of the m-AAA protease in mitochondria. Mol Biol Cell 2007; 18:3582–3590.

    Article  CAS  PubMed  Google Scholar 

  21. Smirnova E, Griparic L, Shurland DL et al. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 2001; 12:2245–2256.

    CAS  PubMed  Google Scholar 

  22. Stojanovski D, Koutsopoulos OS, Okamoto K et al. Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J Cell Sci 2004; 117:1201–1210.

    Article  CAS  PubMed  Google Scholar 

  23. Yoon Y, Krueger EW, Oswald BJ et al. The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol 2003; 23:5409–5420.

    Article  CAS  PubMed  Google Scholar 

  24. James DI, Parone PA, Mattenberger Y et al. hFis1, a novel component of the mammalian mitochondrial fission machinery. J Biol Chem 2003; 278:36373–36379.

    Article  CAS  PubMed  Google Scholar 

  25. Lee YJ, Jeong SY, Karbowski M et al. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1 and Opa1 in apoptosis. Mol Biol Cell 2004; 15:5001–5011.

    Article  CAS  PubMed  Google Scholar 

  26. Chang CR, Blackstone C. Drp1 phosphorylation and mitochondrial regulation. EMBO Rep 2007; 8:1088–1089; author reply 1089–1090.

    Article  CAS  PubMed  Google Scholar 

  27. Harder Z, Zunino R, McBride H. Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr Biol 2004; 14:340–345.

    CAS  PubMed  Google Scholar 

  28. Karbowski M, Neutzner A, Youle RJ. The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. J Cell Biol 2007; 178:71–84.

    Article  CAS  PubMed  Google Scholar 

  29. Nakamura N, Hirose S. Regulation of mitochondrial morphology by USP30, a deubiquitinating enzyme present in the mitochondrial outer membrane. Mol Biol Cell 2008; 19:1903–1911.

    Article  CAS  PubMed  Google Scholar 

  30. Cribbs JT, Strack S. Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep 2007; 8:939–944.

    Article  CAS  PubMed  Google Scholar 

  31. Han XJ, Lu YF, Li SA et al. CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol 2008; 182:573–585.

    Article  CAS  PubMed  Google Scholar 

  32. Taguchi N, Ishihara N, Jofuku A et al. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem 2007; 282:11521–11529.

    Article  CAS  PubMed  Google Scholar 

  33. Gandre-Babbe S, van der Bliek AM. The novel tail-anchored membrane protein Mff controls mitochondrial and peroxisomal fission in mammalian cells. Mol Biol Cell 2008; 19:2402–2412.

    Article  CAS  PubMed  Google Scholar 

  34. Yonashiro R, Ishido S, Kyo S et al. A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics. EMBO J 2006; 25:3618–3626.

    Article  CAS  PubMed  Google Scholar 

  35. Nakamura N, Kimura Y, Tokuda M et al. MARCH-V is a novel mitofusin 2-and Drp1-binding protein able to change mitochondrial morphology. EMBO Rep 2006; 7:1019–1022.

    Article  CAS  PubMed  Google Scholar 

  36. Braschi E, Zunino R, McBride HM. MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission. EMBO Rep 2009; 10:748–754.

    Article  CAS  PubMed  Google Scholar 

  37. Zunino R, Schauss A, Rippstein P et al. The SUMO protease SENP5 is required to maintain mitochondrial morphology and function. J Cell Sci 2007; 120:1178–1188.

    Article  CAS  PubMed  Google Scholar 

  38. Poole AC, Thomas RE, Andrews LA et al. The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA 2008; 105:1638–1643.

    Article  CAS  PubMed  Google Scholar 

  39. Yang Y, Ouyang Y, Yang L et al. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci USA 2008; 105:7070–7075.

    Article  CAS  PubMed  Google Scholar 

  40. Nakada K, Inoue K, Ono T et al. Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nat Med 2001; 7:934–940.

    Article  CAS  PubMed  Google Scholar 

  41. Varadi A, Johnson-Cadwell LI, Cirulli V et al. Cytoplasmic dynein regulates the subcellular distribution of mitochondria by controlling the recruitment of the fission factor dynamin-related protein-1. J Cell Sci 2004; 117:4389–4400.

    Article  CAS  PubMed  Google Scholar 

  42. Twig G, Elorza A, Molina AJ et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 2008; 27:433–446.

    Google Scholar 

  43. Breckenridge DG, Kang BH, Kokel D et al. Caenorhabditis elegans drp-1 and fis-2 regulate distinct cell-death execution pathways downstream of ced-3 and independent of ced-9. Mol Cell 2008; 31:586–597.

    Article  CAS  PubMed  Google Scholar 

  44. Benard G, Bellance N, James D et al. Mitochondrial bioenergetics and structural network organization. J Cell Sci 2007; 120:838–848.

    Article  CAS  PubMed  Google Scholar 

  45. Chen H, Chomyn A, Chan DC. Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 2005; 280:26185–26192.

    Article  CAS  PubMed  Google Scholar 

  46. Tondera D, Grandemange S, Jourdain A et al. SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J 2009; 28:1589–1600.

    Article  CAS  PubMed  Google Scholar 

  47. Davies VJ, Hollins AJ, Piechota MJ et al. Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function. Hum Mol Genet 2007; 16:1307–1318.

    Article  CAS  PubMed  Google Scholar 

  48. Ishihara N, Nomura M, Jofuku A et al. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol 2009, doi:10.1038/ncb1907.

    Google Scholar 

  49. Waterham HR, Koster J, van Roermund CW et al. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med 2007; 356:1736–1741.

    Article  CAS  PubMed  Google Scholar 

  50. Frank S, Gaume B, Bergmann-Leitner ES et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 2001; 1:515–525.

    Article  CAS  PubMed  Google Scholar 

  51. Jagasia R, Grote P, Westermann B et al. DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans. Nature 2005; 433:754–760.

    Article  CAS  PubMed  Google Scholar 

  52. Goyal G, Fell B, Sarin A et al. Role of mitochondrial remodeling in programmed cell death in Drosophila melanogaster. Dev Cell 2007; 12:807–816.

    Article  CAS  PubMed  Google Scholar 

  53. Yamaguchi R, Lartigue L, Perkins G et al. Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis and independent of Bak oligomerization. Mol Cell 2008; 31:557–569.

    Article  CAS  PubMed  Google Scholar 

  54. Brooks C, Wei Q, Feng L et al. Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins. Proc Natl Acad Sci USA 2007; 104:11649–11654.

    Article  CAS  PubMed  Google Scholar 

  55. Arnoult D, Gaume B, Karbowski M et al. Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization. EMBO J 2003; 22:4385–4399.

    Article  CAS  PubMed  Google Scholar 

  56. Sun MG, Williams J, Munoz-Pinedo C et al. Correlated three-dimensional light and electron microscopy reveals transformation of mitochondria during apoptosis. Nat Cell Biol 2007; 9:1057–1065.

    Article  CAS  PubMed  Google Scholar 

  57. John GB, Shang Y, Li L et al. The mitochondrial inner membrane protein mitofilin controls cristae morphology. Mol Biol Cell 2005; 16:1543–1554.

    Article  CAS  PubMed  Google Scholar 

  58. Li H, Chen Y, Jones AF et al. Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci USA 2008; 105:2169–2174.

    Article  CAS  PubMed  Google Scholar 

  59. Liu QA, Shio H. Mitochondrial morphogenesis, dendrite development and synapse formation in cerebellum require both BCL-2 and the glutamate receptor delta2. PLoS Genet 2008; 4:e1000097.

    Article  PubMed  Google Scholar 

  60. Shroff EH, Snyder CM, Budinger GR et al. BH3 peptides induce mitochondrial fission and cell death independent of BAX/BAK. PLoS One 2009; 4:e5646.

    Article  PubMed  Google Scholar 

  61. Karbowski M, Norris KL, Cleland MM et al. Role of Bax and Bak in mitochondrial morphogenesis. Nature 2006; 443:658–662.

    Article  CAS  PubMed  Google Scholar 

  62. Norris KL, Youle RJ. Cytomegalovirus proteins vMIA and m38.5 link mitochondrial morphogenesis to BCL-2 family proteins. J Virol 2008; 82:6232–6243.

    Article  CAS  PubMed  Google Scholar 

  63. Karbowski M, Lee YJ, Gaume B et al. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1 and Mfn2 during apoptosis. J Cell Biol 2002; 159:931–938.

    Article  CAS  PubMed  Google Scholar 

  64. Wasiak S, Zunino R, McBride HM: Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J Cell Biol 2007; 177:439–450.

    Article  CAS  PubMed  Google Scholar 

  65. Cassidy-Stone A, Chipuk JE, Ingerman E et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 2008; 14:193–204.

    Article  CAS  PubMed  Google Scholar 

  66. Parone PA, James DI, Da Cruz S et al. Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis. Mol Cell Biol 2006; 26:7397–7408.

    Article  CAS  PubMed  Google Scholar 

  67. Brooks C, Wei Q, Cho SG et al. Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J Clin Invest 2009; 119:1275–1285.

    Article  CAS  PubMed  Google Scholar 

  68. Sugioka R, Shimizu S, Tsujimoto Y. Fzo1, a protein involved in mitochondrial fusion, inhibits apoptosis. J Biol Chem 2004; 279:52726–52734.

    Article  CAS  PubMed  Google Scholar 

  69. Berman SB, Chen Y-b, Qi B et al. Bcl-xL increases mitochondrial fission, fusion and biomass in neurons. J Cell Biol 2009; 184:10.1083/jcb.200809060.

    Article  Google Scholar 

  70. Tan FJ, Husain M, Manlandro CM et al. CED-9 and mitochondrial homeostasis in C. elegans muscle. J Cell Sci 2008; 121:3373–3382.

    Article  CAS  PubMed  Google Scholar 

  71. Breckenridge DG, Kang BH, Xue D. BCL-2 proteins EGL-1 and CED-9 do not regulate mitochondrial fission or fusion in Caenorhabditis elegans. Curr Biol 2009; 19:768–773.

    Article  CAS  PubMed  Google Scholar 

  72. Delivani P, Adrain C, Taylor RC et al. Role for CED-9 and Egl-1 as regulators of mitochondrial fission and fusion. Mol Cell 2006; 21:761–773.

    Article  CAS  PubMed  Google Scholar 

  73. Sheridan C, Delivani P, Cullen SP et al. Bax-or Bak-induced mitochondrial fission can be uncoupled from cytochrome C release. Mol Cell 2008; 31:570–585.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Medical Biotechnology Center, University of Maryland Biotechnology Institute, 725 W. Lombard St, Baltimore, Maryland, 21201, USA

    Mariusz Karbowski

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  1. Mariusz Karbowski
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Editors and Affiliations

  1. Institute of Biomedical Sciences, FONDAP Center for Molecular Studies of the Cell (CEMC) Millennium Nucleus for Neural Morphogenesis (NEMO), University of Chile, Santiago, Chile

    Claudio Hetz PhD

  2. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA

    Claudio Hetz PhD

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Karbowski, M. (2010). Mitochondria on Guard: Role of Mitochondrial Fusion and Fission in the Regulation of Apoptosis. In: Hetz, C. (eds) BCL-2 Protein Family. Advances in Experimental Medicine and Biology, vol 687. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6706-0_8

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