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Mitochondria and Apoptosis: HQ or High-Security Prison?

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Abstract

Whether we view the mitochondria as the headquarters for the leader of a crack suicide squad or as a prison for the leader of a militant coup, the role of the mitochondria in the apoptotic process is now well established. During apoptosis the integrity of the mitochondria is breeched, the mitochondrial transmembrane potential drops, the electron transport chain is disrupted, and proteins from the mitochondrial intermembrane space (MIS) such as cytochrome c are released into the cytosol, although not necessarily in that order. In the cytosol, cytochrome c forms part of a proteinaceous complex that directly activates caspase-9, one of the apical enzymes responsible for the dismantling of the cell. In this way a mitochondrial factor which is normally locked away from the rest of the cell can directly trigger apoptosis. The need to regulate the release of cytochrome c suggests that the mitochondria may be the decision center for whether a cell lives or dies. Various hypotheses have been formulated to explain how proteins of the MIS are released and how this process is regulated. These include the Bcl-2-regulated opening of a permeability transition pore or an increase in mitochondrial transmembrane potential followed by outer membrane rupture. It remains to be clarified which mitochondria specific events are essential for apoptosis and which are merely consequences of apoptosis.

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REFERENCES

  1. Badley AD, Cameron DW, Kravcik S, Phenix BN, Ashby D, Kumar A, Lynch DH, Tschopp J: Dynamic correlation of apoptosis and immune activation during treatment of HIV infection. Cell Death Different 6:420–432, 1999

    Google Scholar 

  2. Ishizaki Y, Cheng L, Mudge AW, Raff MC: Programmed cell death by default in embryonic cells, fibroblasts, and cancer cells. Mol Biol Cell 6:1443–1458, 1995

    Google Scholar 

  3. Ohsako S, Elkon KB: Apoptosis in the effector phase of autoimmune diabetes, multiple sclerosis and thyroiditis. Cell Death Different 6:13–21, 1999

    Google Scholar 

  4. Roy N, Mahadevan MS, McLean M, Shutler G, Yaraghi Z, Farahani R, Baird S, Besner-Johnston A, Lefebvre C, Kang X, Salih M, Aubry H, Tamai K, Guan X, Ioannou P, Crawford T, deJong P, Surh L, Ikeda J, Korneluk R, MacKenzie A: The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80:167–178, 1995

    Google Scholar 

  5. Thompson CB: Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462, 1995

    Google Scholar 

  6. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW: Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985–988, 1995

    Google Scholar 

  7. Yuan J: Transducing signals of life and death. Curr Opin Cell Biol 9:247–251, 1997

    Google Scholar 

  8. Wolvetang EJ, Johnson KL, Krauer K, Ralph SJ, Linnane AW: Mitochondrial respiratory chain inhibitors induce apoptosis. FEBS Lett 339:40–44, 1994

    Google Scholar 

  9. McCarthy NJ, Whyte MK, Gilbert CS, Evan GI: Inhibition of Ced-3/ICE-related proteases does not prevent cell death induced by oncogenes, DNA damage, or the Bcl-2 homologue Bak. J Cell Biol 136:215–227, 1997

    Google Scholar 

  10. Martin SJ, Finucane DM, Amarante-Mendes GP, O'Brien GA, Green DR: Phosphatidylserine externalization during CD95-induced apoptosis of cells and cytoplasts requires ICE/CED-3 protease activity. J Biol Chem 271:28753–28756, 1996

    Google Scholar 

  11. Watters D, Waterhouse N: Proteolytic targets in cell death. Results Probl Cell Different 24:25–44, 1998

    Google Scholar 

  12. Sakahira H, Enari M, Nagata S: Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391:96–99, 1998

    Google Scholar 

  13. Martin SJ, O'Brien GA, Nishioka WK, McGahon AJ, Mahboubi A, Saido TC, Green DR: Proteolysis of fodrin (non-erythroid spectrin) during apoptosis. J Biol Chem 270:6425–6428, 1995

    Google Scholar 

  14. Kothakota S, Azuma T, Reinhard C, Klippel A, Tang J, Chu K, McGarry TJ, Kirschner MW, Koths K, Kwiatkowski DJ, Williams LT: Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science 278:294–298, 1997

    Google Scholar 

  15. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD: The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science 275:1132–1136, 1997

    Google Scholar 

  16. Kluck RM, Martin SJ, Hoffman BM, Zhou JS, Green DR, Newmeyer DD: Cytochrome c activation of CPP32-like proteolysis plays a critical role in a Xenopus cell-free apoptosis system. EMBO J 16:4639–4649, 1997

    Google Scholar 

  17. Gray MW, Burger G, Lang BF: Mitochondrial evolution. Science 283:1476–1481, 1999

    Google Scholar 

  18. Wyllie AH: What is apoptosis? Histopathology 10:995–998, 1986

    Google Scholar 

  19. Hengartner MO, Horvitz HR: Programmed cell death in Caenorhabditis elegans. Curr Opin Genet Dev 4:581–586, 1994

    Google Scholar 

  20. Medema JP, Scaffidi C, Kischkel FC, Shevchenko A, Mann M, Krammer PH, Peter ME: FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 16:2794–2804, 1997

    Google Scholar 

  21. Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM: FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85:817–827, 1996

    Google Scholar 

  22. Jacobson MD, Burne JF, King MP, Miyashita T, Reed JC, Raff MC: Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA. Nature 361:365–369, 1993

    Google Scholar 

  23. Nakajima H, Golstein P, Henkart PA: The target cell nucleus is not required for cell-mediated granzyme-or Fas-based cytotoxicity. J Exp Med 181:1905–1909, 1995

    Google Scholar 

  24. Jacobson MD, Burne JF, Raff MC: Programmed cell death and Bcl-2 protection in the absence of a nucleus. EMBO J 13:1899–1910, 1994

    Google Scholar 

  25. Newmeyer DD, Farschon DM, Reed JC: Cell-free apoptosis in Xenopus egg extracts: Inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria. Cell 79:353–364, 1994

    Google Scholar 

  26. Hengartner MO, Horvitz HR: C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76:665–676, 1994

    Google Scholar 

  27. Nguyen M, Millar DG, Yong VW, Korsmeyer SJ, Shore GC: Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence. J Biol Chem 268:25265–25268, 1993

    Google Scholar 

  28. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G: Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446, 1999

    Google Scholar 

  29. Susin SA, Zamzami N, Castedo M, Hirsch T, Marchetti P, Macho A, Daugas E, Geuskens M, Kroemer G: Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J Exp Med 184:1331–1341, 1996

    Google Scholar 

  30. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X: Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90:405–413, 1997

    Google Scholar 

  31. Zou H, Li Y, Liu X, Wang X: An APAF-1 cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 274:11549–11556, 1999

    Google Scholar 

  32. Hu Y, Benedict MA, Ding L, NG: Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J 18:3586–3595, 1999

    Google Scholar 

  33. Saleh A, Srinivasula SM, Acharya S, Fishel R, Alnemri ES: Cytochrome c and dATP-mediated oligomerization of Apaf-1 is a prerequisite for procaspase-9 activation. J Biol Chem 274:17941–17945, 1999

    Google Scholar 

  34. Stennicke HR, Deveraux QL, Humke EW, Reed JC, Dixit VM, Salvesen GS: Caspase-9 can be activated without proteolytic processing. J Biol Chem 274:8359–8362, 1999

    Google Scholar 

  35. Song Q, Kuang Y, Dixit VM, Vincenz C: Boo, a novel negative regulator of cell death, interacts with Apaf-1. EMBO J 18:167–178, 1999

    Google Scholar 

  36. Inohara N, Gourley TS, Carrio R, Muniz M, Merino J, Garcia I, Koseki T, Hu Y, Chen S, Nunez G: Diva, a Bcl-2 homologue that binds directly to Apaf-1 and induces BH3-independent cell death. J Biol Chem 273:32479–32486, 1998

    Google Scholar 

  37. Tsujimoto Y: Role of Bcl-2 family proteins in apoptosis: Apoptosomes or mitochondria? Genes Cells 3:697–707, 1998

    Google Scholar 

  38. Martinou I, Desagher S, Eskes R, Antonsson B, Andre E, Fakan S, Martinou JC: The release of cytochrome c from mitochondria during apoptosis of NGF-deprived sympathetic neurons is a reversible event. J Cell Biol 144:883–889, 1999

    Google Scholar 

  39. Moriishi K, Huang DC, Cory S, Adams JM: Bcl-2 family members do not inhibit apoptosis by binding the caspase activator Apaf-1. Proc Natl Acad Sci USA 96:9683–9688, 1999

    Google Scholar 

  40. Li H, Zhu H, Xu CJ, Yuan J: Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501, 1998

    Google Scholar 

  41. Kuwana T, Smith JJ, Muzio M, Dixit V, Newmeyer DD, Kornbluth S: Apoptosis induction by caspase-8 is amplified through the mitochondrial release of cytochrome c. J Biol Chem 273:16589–16594, 1998

    Google Scholar 

  42. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Brenner C, Larochette N, Prevost MC, Alzari PM, Kroemer G: Mitochondrial release of caspase-2 and-9 during the apoptotic process. J Exp Med 189:381–394, 1999

    Google Scholar 

  43. Samali A, Cai J, Zhivotovsky B, Jones DP, Orrenius S: Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells. EMBO J 18:2040–2048, 1999

    Google Scholar 

  44. Kohler C, Gahm A, Noma T, Nakazawa A, Orrenius S, Zhivotovsky B: Release of adenylate kinase 2 from the mitochondrial intermembrane space during apoptosis. FEBS Lett 447:10–12, 1999

    Google Scholar 

  45. Reed JC: Double identity for proteins of the Bcl-2 family. Nature 387:773–776, 1997

    Google Scholar 

  46. Crompton M: The mitochondrial permeability transition pore and its role in cell death. Biochem J 341:233–249, 1999

    Google Scholar 

  47. Huser J, Rechenmacher CE, Blatter LA: Imaging the permeability pore transition in single mitochondria. Biophys J 74:2129–2137, 1998

    Google Scholar 

  48. Reed PW: Inophores. Methods Enzymol 55:435–454, 1979

    Google Scholar 

  49. Zamzami N, Susin SA, Marchetti P, Hirsch T, Gomez-Monterrey I, Castedo M, Kroemer G: Mitochondrial control of nuclear apoptosis. J Exp Med 183:1533–1544, 1996

    Google Scholar 

  50. Marchetti P, Castedo M, Susin SA, Zamzami N, Hirsch T, Macho A, Haeffner A, Hirsch F, Geuskens M, Kroemer G: Mitochondrial permeability transition is a central coordinating event of apoptosis. J Exp Med 184:1155–1160, 1996

    Google Scholar 

  51. Hirsch T, Susin SA, Marzo I, Marchetti P, Zamzami N, Kroemer G: Mitochondrial permeability transition in apoptosis and necrosis. Cell Biol Toxicol 14:141–145, 1998

    Google Scholar 

  52. Lemasters JJ, Nieminen AL, Qian T, Trost LC, Elmore SP, Nishimura Y, Crowe RA, Cascio WE, Bradham CA, Brenner DA, Herman B: The mitochondrial permeability transition in cell death: A common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta 1366:177–196, 1998

    Google Scholar 

  53. Bradham CA, Qian T, Streetz K, Trautwein C, Brenner DA, Lemasters JJ: The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release. Mol Cell Biol 18:6353–6364, 1998

    Google Scholar 

  54. Szabo I, Zoratti M: The mitochondrial permeability transition pore may comprise VDAC molecules. I. Binary structure and voltage dependence of the pore. FEBS Lett 330:201–205, 1993

    Google Scholar 

  55. Krajewski S, Tanaka S, Takayama S, Schibler MJ, Fenton W, Reed JC: Investigation of the subcellular distribution of the bcl-2 oncoprotein: Residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res 53:4701–4714, 1993

    Google Scholar 

  56. Shimizu S, Narita M, Tsujimoto Y: Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483–487, 1999

    Google Scholar 

  57. Marzo I, Zamzami BC, Jurgensmeier JM, Susin SA, Vieira HL, Prevost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G: Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281:2027–2031, 1998

    Google Scholar 

  58. Murphy AN, Bredesen DE, Cortopassi G, Wang E, Fiskum G: Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc Natl Acad Sci USA 93:9893–9898, 1996

    Google Scholar 

  59. Andreyev AY, Fiskum G: Cytochrome c release from brain mitochondria is independent of the mitochondrial permeability transition. FEBS Lett 439:373–376, 1998

    Google Scholar 

  60. Bossy-Wetzel E, Newmeyer DD, Green DR: Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 17:37–49, 1998

    Google Scholar 

  61. Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR: Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J Biol Chem 274:2225–2233, 1999

    Google Scholar 

  62. Eskes R, Antonsson B, Osen-Sand A, Montessuit S, Richter C, Sadoul R, Mazzei G, Nichols A, Martinou JC: Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions. J Cell Biol 143:217–224, 1998

    Google Scholar 

  63. Finucane DM, Waterhouse NJ, Amarante-Mendes GP, Cotter TG, Green DR: Collapse of the inner mitochondrial transmembrane potential is not required for apoptosis of HL60 cells. Exp Cell Res 251:166–174, 1999

    Google Scholar 

  64. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X: Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489, 1997

    Google Scholar 

  65. Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P, Flavell RA: Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94:325–337, 1998

    Google Scholar 

  66. Chandel NS, Schumacker PT: Cells depleted of mitochondrial DNA (rho0) yield insight into physiological mechanisms. FEBS Lett 454:173–176, 1999

    Google Scholar 

  67. La Piana G, Fransvea E, Marzulli D, Lofrumento NE: Mitochondrial membrane potential supported by exogenous cytochrome c oxidation mimics the early stages of apoptosis. Biochem Biophys Res Commun 246:556–561, 1998

    Google Scholar 

  68. Ravagnan L, Marzo I, Costantini P, Susin SA, Zamzami N, Petit PX, Hirsch F, Goulbern M, Poupon MF, Miccoli L, Xie, Z, Reed JC, Kroemer G: Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore. Oncogene 18:2537–2546, 1999

    Google Scholar 

  69. Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB: Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell 91:627–637, 1997

    Google Scholar 

  70. Heiden MG, Chandel NS, Schumacker PT, Thompson CB: Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. Mol Cell 3:159–167, 1999

    Google Scholar 

  71. Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS, Nettesheim D, Chang BS, Thompson CB, Wong SL, Ng SL, Fesik SW: X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 381:335–341, 1996

    Google Scholar 

  72. Antonsson B, Conti F, Ciavatta A, Montessuit S, Lewis S, Martinou I, Bernasconi L, Bernard A, Mermod JJ, Mazzei G, Maundrell K, Gambale F, Sadoul R, Martinou JC: Inhibition of Bax channel-forming activity by Bcl-2. Science 277:370–372, 1997

    Google Scholar 

  73. Minn AJ, Velez P, Schendel SL, Liang H, Muchmore SW, Fesik SW, Fill M, Thompson CB: Bcl-x(L) forms an ion channel in synthetic lipid membranes. Nature 385:353–357, 1997

    Google Scholar 

  74. Schendel SL, Xie Z, Montal MO, Matsuyama S, Montal M, Reed JC: Channel formation by antiapoptotic protein Bcl-2. Proc Natl Acad Sci USA 94:5113–5118, 1997

    Google Scholar 

  75. Schendel SL, Azimov R, Pawlowski K, Godzik A, Kagan BL, Reed JC: Ion channel activity of the BH3 only bcl-2 family member, BID. J Biol Chem 274:21932–21936, 1999

    Google Scholar 

  76. Schendel SL, Montal M, Reed JC: Bcl-2 family proteins as ion-channels. Cell Death Different 5:372–380, 1998

    Google Scholar 

  77. Basanez G, Nechushtan A, Drozhinin O, Chanturiya A, Choe E, Tutt S, Wood KA, Hsu Y, Zimmerberg J, Youle RJ: Bax, but not Bcl-xL, decreases the lifetime of planar phospholipid bilayer membranes at subnanomolar concentrations. Proc Natl Acad Sci USA 96:5492–5497, 1999

    Google Scholar 

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  1. Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, California, 92121

    Nigel J. Waterhouse & Douglas R. Green

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Waterhouse, N.J., Green, D.R. Mitochondria and Apoptosis: HQ or High-Security Prison?. J Clin Immunol 19, 378–387 (1999). https://doi.org/10.1023/A:1020550716138

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