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Mitochondrial Function in Apoptotic Neuronal Cell Death

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Abstract

Apoptosis can be defined as the regulated death of a cell and is conducted by conserved pathways. Apoptosis of neurons after injury or disease differs from programed cell death, in the sense that neurons in an adult brain are not “meant” to die and results in a loss of function. Thus apoptosis is an honorable process by a neuron, a cell with limited potential to replace itself, choosing instead to commit suicide to save neighboring cells from release of cellular components that cause injury directly or trigger secondary injury resulting from inflammatory reactions. The excess of apoptosis of neuronal cells underlies the progressive loss of neuronal populations in neurodegenerative disorders and thus is harmful. Mitochondria are the primary source for energy in neurons but are also poised, through the “mitochondrial apoptosis pathway,” to signal the demise of cells. This duplicity of mitochondria is discussed, with particular attention given to the specialized case of pathological neuronal cell death.

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References

  1. Kerr, J. F., Wyllie, A. H., and Currie, A. R. 1972. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26:239–247.

    PubMed  Google Scholar 

  2. Wyllie, A. H., Kerr, J. F. R., and Currie, A. R. 1980. Cell death: The significance of apoptosis. Intl. Rev. Cytol. 68:251–306.

    Google Scholar 

  3. Pettmann, B. and Henderson, C. E. 1998. Neuronal cell death. Neuron 20:633–647.

    PubMed  Google Scholar 

  4. Peiper, A. A., Verma, A., Zhang, J., and Snyder, S. H. 1999. Poly (ADP-ribose) polymerase, nitric oxide and cell death. TiPS 20:171–181.

    PubMed  Google Scholar 

  5. Wang, K. K. W. 2000. Calpain and caspase: Can you tell the difference? TiNS 23:20–26.

    PubMed  Google Scholar 

  6. Kaufmann, S. H. and Hengartner, M. O. 2001 Programmed cell death: Alive and well in the new millennium. Trends Cell Biol. 11:526–534.

    PubMed  Google Scholar 

  7. Juo, P., Kuo, C. J., Yuan, J., and Blenis, J. 1998. Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade. Curr. Biol. 8:1001–1008.

    PubMed  Google Scholar 

  8. Liu, X., Kim, C. N., Yang, J., Jemmerson, R., and Wang, X. 1996. Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c. Cell 86:147–157.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  10. Martinou, J. C., Desagher, S., and Antonsson, B. 2000. Cytochrome c release from mitochondria: All or nothing. Nat. Cell Biol. 2:E41–E43.

    PubMed  Google Scholar 

  11. Chauhan, D., Li, G., Hideshima, T., Podar, K., Mitsiades, C., Mitsiades, N., Munshi, N., Kharbanda, S., and Anderson, K. C. 2003. JNK-dependent release of mitochondrial protein, SMAC during apoptosis in multiple myeloma (MM) cells. J. Biol. Chem. (Mar 28 epub ahead of print).

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

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  14. Nicotera, P., Leist, M., and Manzo, L. 1999. Neuronal cell death: A demise with different shapes. TiPS 20:46–51.

    PubMed  Google Scholar 

  15. Bonetti, B. and Raine, C. S. 1997. Multiple sclerosis: Oligodendrocytes display cell death-related molecules in situ but do not undergo apoptosis. Ann. Neurol. 42:74–84.

    PubMed  Google Scholar 

  16. Sohn, S., Kim, E. Y., and Gwag, B. J. 1998. Glutamate neurotoxicity in mouse cortical neurons: Atypical necrosis with DNA ladders and chromatin condensation. Neurosci. Lett. 240:147–150.

    PubMed  Google Scholar 

  17. Leist, M. and Nicotera, P. 1998. Apoptosis, excitotoxicity, and neuropathology. Exp. Cell Res. 239:183–201.

    PubMed  Google Scholar 

  18. Duvall, E., Wyllie, A. H., and Morris, R. G. 1985. Macrophage recognition of cells undergoing programmed cell death (apoptosis). Immunology 56:351–358.

    PubMed  Google Scholar 

  19. Nicotera, P., Leist, M., Fava, E., Berliocchi, L., and Volbracht, C. 2000. Energy requirement for caspase activation and neuronal cell death. Brain Pathol. 10:276–282.

    PubMed  Google Scholar 

  20. Choi, D. W. and Rothman, S. M. 1990. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Ann. Rev. Neurosci. 13:171–182.

    PubMed  Google Scholar 

  21. Nitatori, T., Sato, N., Waguri, S., Karasawa, Y., Araki, H., Shibanai, K., Kominami, E., and Uchiyama, Y. 1995. Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J. Neurosci. 15:1001–1011.

    PubMed  Google Scholar 

  22. Choi, D. W. 1996. Neurobiology of disease. Curr. Opin. Neurobiol. 6:667–672.

    PubMed  Google Scholar 

  23. Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P., and Lipton, S. A. 1995. Apoptosis and necrosis: Two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc. Natl. Acad. Sci. USA 92:7162–7166.

    PubMed  Google Scholar 

  24. Hartley, D. M., Kurth, M. C., Bjerkness, L., Weiss, J. H., and Choi, D. W. 1993. Glutamate receptor-induced 45Ca2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration. J. Neurosci. 13:1993–2000.

    PubMed  Google Scholar 

  25. Rondouin, G., Drian, M. J., Chicheportiche, R., Kamenka, J. M., and Privat, A. 1998. Non-competitive antagonists of N-methyl-D-aspartate receptors protect cortical and hippocampal cell cultures against glutamate neurotoxicity. Neurosci. Lett. 91:199–203.

    Google Scholar 

  26. Choi, D. W., Maulucci-Gedde, M., and Kriegstein, A. R. 1987. Glutamate neurotoxicity in cortical cell culture. J. Neurosci. 7:357–368.

    PubMed  Google Scholar 

  27. Budd, S. L. and Nicholls, D. G. 1996. Mitochondria, calcium regulation, and acute glutamate excitotoxicity in cultured cerebellar granule cells. J. Neurochem. 67:2282–2291.

    PubMed  Google Scholar 

  28. Slagsvold, H. H., Marvik, O. J., Eidem, G., Kristoffersen, N., and Paulsen, R. E. 2000. Detection of high molecular weight DNA fragments characteristic of early stage apoptosis in cerebellar granule cells exposed to glutamate. Exp. Brain Res. 135:173–178.

    PubMed  Google Scholar 

  29. Gwag, B. J., Koh, J. Y., DeMaro, J. A., Ying, H. S., Jacquin, M., and Choi, D. W. 1997. Slowly triggered excitotoxicity occurs by necrosis in cortical cultures. Neuroscience 77:393–401.

    PubMed  Google Scholar 

  30. Ankarcrona, M., Dypbukt, J. M., Bonfoco, E., Zhivotovsky, B., Orrenius, S., Lipton, S. A., and Nicotera, P. 1995. Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15:961–973.

    PubMed  Google Scholar 

  31. Plaetzer, K., Kiesslich, T., Krammer, B., and Hammerl, P. 2002. Characterization of the cell death modes and the associated changes in cellular energy supply in response to AIPcS4-PDT. Photochem. Photobiol. Sci. 1:172–177.

    PubMed  Google Scholar 

  32. Leist, M., Single, B., Castoldi, A. F., Kuhnle, S., and Nicotera, P. 1997. Intracellular adenosine triphosphate (ATP) concentration: A switch in the decision between apoptosis and necrosis. J. Exp. Med. 185:1481–1486.

    PubMed  Google Scholar 

  33. Grusch, M., Polgar, D., Gfatter, S., Leuhuber, K., Huettenbrenner, S., Leisser, C., Fuhrmann, G., Kassie, F., Steinkellner, H., Smid, K., Peters, G. J., Jayaram, H. N., Klopal, W., Szekeres, T., Knasmuller, S., and Krupitza, G. 2002. Maintenance of ATP favours apoptosis over necrosis triggered by benzamide riboside. Cell. Death Differ. 9:169–178.

    PubMed  Google Scholar 

  34. Stridh, H., Fava, E., Single, B., Nicotera, P., Orrenius, S., and Leist, M. 1999. Tributyltin-induced apoptosis requires glycolytic adenosine trisphosphate production. Chem. Res. Toxicol. 12:874–882.

    PubMed  Google Scholar 

  35. Kim, J. S., Qian, T., and Lemasters, J. J. 2003. Mitochondrial permeability transition in the switch from necrotic to apoptotic cell death in ischemic rat hepatocytes. Gastroenterology 124:494–503.

    PubMed  Google Scholar 

  36. Delgado-Esteban, M., Almeida, A., and Bolanos, J. P. 2000. D-Glucose prevents glutathione oxidation and mitochondrial damage after glutamate receptor stimulation in rat cortical primary neurons. J. Neurochem. 75:1618–1624.

    PubMed  Google Scholar 

  37. Budd, S. L., Tenneti, L., Lishnak, T., and Lipton, S. A. 2000. Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons. Proc. Natl. Acad. Sci. USA 97:6161–6166.

    PubMed  Google Scholar 

  38. Calabrese, V., Scapagnini, G., Giuffrida Stella, A. M., Bates, T. E., and Clark, J. B. 2001. Mitochondrial involvement in brain function and dysfunction: Relevance to aging, neurodegenerative disorders and longevity. Neurochem. Res. 26:739–764.

    PubMed  Google Scholar 

  39. Martin, D. P., Schmidt, R. E., DiStefano, P. S., Lowry, O. H., Carter, J. G., and Johnson, E. M. Jr. 1988. Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation. J. Cell Biol. 106:829–844.

    PubMed  Google Scholar 

  40. Watson, A., Eilers, A., Lallemand, D., Kyriakis, J., Rubin, L. L., and Ham, J. 1998. Phosphorylation of c-Jun is necessary for apoptosis induced by survival signal withdrawal in cerebellar granule neurons. J. Neurosci. 18:751–762.

    PubMed  Google Scholar 

  41. D'Mello, S. R., Galli, C., Ciotti, T., and Calissano, P. 1993. Induction of apoptosis in cerebellar granule neurons by low potassium: Inhibition of death by insulin-like growth factor I and cAMP. Proc. Natl. Acad. Sci. USA 90:10989–10993.

    PubMed  Google Scholar 

  42. Hong, H. N., Yoon, S. Y., Suh, J., Lee, J. H., and Kim, D. 2002. Differential activation of caspase-3 at two maturational stages during okadaic acid-induced rat neuronal death. Neurosci. Lett. 334:63–67.

    PubMed  Google Scholar 

  43. McCollum, A. T., Nasr, P., and Estus, S. 2002. Calpain activates caspase-3 during UV-induced neuronal death but only calpain is necessary for death. J. Neurochem. 82:1208–1220.

    PubMed  Google Scholar 

  44. Özören, N. and El-Deiry, W. S. 2002. Defining characteristics of types I and II apoptotic cells in response to TRAIL. Neoplasia 4:551–557.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  46. Elledge, S. J., Zhou, Z., and Allen, J. B. 1992. Ribonucleotide reductase: Regulation, regulation, regulation. Trends Biochem. Sci. 17:119–123.

    PubMed  Google Scholar 

  47. Brockhaus, F. and Brune, B. 1999. p53 accumulation in apoptotic macrophages is an energy demanding process that precedes cytochrome c release in response to nitric oxide. Oncogene 18:6403–6410.

    PubMed  Google Scholar 

  48. Du, C., Fang, M., Li, Y., Li, L., and Wang, X. 2000. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102:33–42.

    PubMed  Google Scholar 

  49. Hegde, R., Srinivasula, S. M., Zhang, Z., Wassell, R., Mukattash, R., Cilenti, L., DuBois, G., Lazebnik, Y., Zervos, A. S., Fernandes-Alnemri, T., and Alnemri, E. S. 2002. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J. Biol. Chem. 277:432–438.

    PubMed  Google Scholar 

  50. Martins, L. M., Iaccarino, I., Tenev, T., Gschmeissner, S., Totty, N. F., Lemoine, N. R., Savopoulos, J., Gray, C. W., Creasy, C. L., Dingwall, C., and Downward, J. 2002. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J. Biol. Chem. 277:439–444.

    PubMed  Google Scholar 

  51. Verhagen, A. M., Silke, J., Ekert, P. G., Pakusch, M., Kaufmann, H., Connolly, L. M., Day, C. L., Tikoo, A., Burke, R., Wrobel, C., Moritz, R. L., Simpson, R. J., and Vaux, D. L. 2002. HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J. Biol. Chem. 277:445–454.

    PubMed  Google Scholar 

  52. Li, L. Y., Luo, X., and Wang, X. 2001. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412:95–99.

    PubMed  Google Scholar 

  53. Parrish, J., Li, L., Klotz, K., Ledwich, D., Wang, X., and Xue, D. 2001. Mitochondrial endonuclease G is important for apoptosis in C. elegans. Nature 412:90–94.

    PubMed  Google Scholar 

  54. Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., Brothers, G. M., Mangion, J., Jacotot, E., Costantini, P., Loeffler, M., Larochette, N., Goodlett, D. R., Aebersold, R., Siderovski, D. P., Penninger, J. M., and Kroemer, G. 1999. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446.

    PubMed  Google Scholar 

  55. Costantini, P., Bruey, J. M., Castedo, M., Metivier, D., Loeffler, M., Susin, S. A., Ravagnan, L., Zamzami, N., Garrido, C., and Kroemer, G. 2002. Pre-processed caspase-9 contained in mitochondria participates in apoptosis. Cell. Death Differ. 9:82–88.

    PubMed  Google Scholar 

  56. Krajewski, S., Krajewska, M., Ellerby, L. M., Welsh, K., Xie, Z., Deveraux, Q. L., Salvosen, G. S., Bredesen, D. E., Rosonthal, R. E., and Reed, J. C. 1999. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc. Natl. Acad. Sci. USA 96:5752–5757.

    PubMed  Google Scholar 

  57. van Loo, G., Saelens, X., Matthijssens, F., Schotte, P., Beyaert, R., Declercq, W., and Vandenabeele, P. 2002. Caspases are not localized in mitochondria during life or death. Cell. Death Differ. 9:1207–1211.

    PubMed  Google Scholar 

  58. Kharbanda, S., Pandey, P., Schofield, L., Israels, S., Roncinske, R., Yoshida, K., Bharti, A., Yuan, Z. M., Saxena, S., Weichselbaum, R., Nalin, C., and Kufe, D. 1997. Role for Bcl-xL as an inhibitor of cytosolic cytochrome c accumulation in DNA damage-induced apoptosis. Proc. Natl. Acad. Sci. USA 94:6939–6942.

    PubMed  Google Scholar 

  59. Kim, C. N., Wang, X., Huang, Y., Ibrado, A. M., Liu, L., Fang, G., and Bhalla, K. 1997. Overexpression of Bcl-X(L) inhibits Ara-C-induced mitochondrial loss of cytochrome c and other perturbations that activate the molecular cascade of apoptosis. Cancer Res. 57:3115–3120.

    PubMed  Google Scholar 

  60. Kluck, R. M., Martin, S. J., Hoffman, B. M., Zhou, J. S., Green, D. R., and Newmeyer, D. D. 1997. Cytochrome c activation of CPP32-like proteolysis plays a critical role in a Xenopus cell-free apoptosis system. EMBO J. 16:4639–4649.

    PubMed  Google Scholar 

  61. Martin, A. G. and Fearnhead, H. O. 2002. Apocytochrome c blocks caspase-9 activation and Bax-induced apoptosis. J. Biol. Chem. 277:50834–50841.

    PubMed  Google Scholar 

  62. Yang, J., Liu, X., Bhalla, K., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T., Jones, D. P., and Wang, X. 1997. Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science 275:1129–1132.

    PubMed  Google Scholar 

  63. Hampton, M. B., Zhivotovsky, B., Slater, A. F., Burgess, D. H., and Orrenius, S. 1998. Importance of the redox state of cytochrome c during caspase activation in cytosolic extracts. Biochem. J. 329:95–99.

    PubMed  Google Scholar 

  64. Purring-Koch, C. and McLendon, G. 2000 Cytochrome c binding to Apaf-1: The effects of dATP and ionic strength. Proc. Natl. Acad. Sci. USA 97:11928–11931.

    PubMed  Google Scholar 

  65. Wigdal, S. S., Kirkland, R. A., Franklin, J. L., and Haak-Frendscho, M. 2002. Cytochrome c release precedes mitochondrial membrane potential loss in cerebellar granule neuron apoptosis: Lack of mitochondrial swelling. J. Neurochem. 82:1029–1038.

    PubMed  Google Scholar 

  66. Deshmukh, D., Kuida, K., and Johnson, E. M. Jr. 2000. Caspase inhibition extends the commitment to neuronal death beyond cytochrome c release to the point of mitochondrial depolarization. J. Cell. Biol. 150.1.131.

  67. Zhang, C., Shen, W., and Zhang, G. 2002. N-Methyl-D-aspartate receptor and L-type voltage-gated Ca(2+) channel antagonists suppress the release of cytochrome c and the expression of procaspase-3 in rat hippocampus after global brain ischemia. Neurosci. Lett. 328:265–268.

    PubMed  Google Scholar 

  68. Zhao, H., Yenari, M. A., Cheng, D., Sapolsky, R. M., and Steinberg, G. K. 2003. Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. J. Neurochem. 85:1026–1028.

    PubMed  Google Scholar 

  69. Kiechle, T., Dedeoglu, A., Kubilus, J., Kowall, N. W., Beal, M. F., Friedlander, R., Hersch, S. M., and Ferrante, R. J. 2002. Cytochrome c and caspase-9 expression in Huntington's disease. Neuromol. Med. 1:183–195.

    Google Scholar 

  70. Loeffler, M., Daugas, E., Susin, S. A., Zamzami, N., Metivier, D., Nieminen, A. L., Brothers, G., Penninger, J. M., and Kroemer, G. 2001. Dominant cell death induction by extramitochondrially targeted apoptosis-inducing factor. FASEB J. 15:758–767.

    PubMed  Google Scholar 

  71. Braun, J. S., Novak, R., Murray, P. J., Eischen, C. M., Susin, S. A., Kroemer, G., Halle, A., Weber, J. R., Tuomanen, E. I., and Cleveland, J. L. 2001. Apoptosis-inducing factor mediates microglial and neuronal apoptosis caused by pneumococcus. J. Infect. Dis. 184:1300–1309.

    PubMed  Google Scholar 

  72. Cregan, S. P., Fortin, A., MacLaurin, J. G., Callaghan, S. M., Cecconi, F., Yu, S. W., Dawson, T. M., Dawson, V. L., Park, D. S., Kroemer, G., and Slack, R. S. 2002. Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death. J. Cell. Biol. 158:507–517.

    PubMed  Google Scholar 

  73. Zhang, X., Chen, J., Graham, S. H., Du, L., Kochanek, P. M., Draviam, R., Guo, F., Nathaniel, P. D., Szabo, G., Watkins, S. C., and Clark, R. S. 2002. Intranuclear localization of apoptosis-inducing factor (AIF) and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite. J. Neurochem. 82:181–191.

    PubMed  Google Scholar 

  74. Du, L., Zhang, X., Han, Y. Y., Burke, N. A., Kochanek, P. M., Watkins, S. C., Graham, S. H., Carcillo, J. A., Szabo, C., and Clark, R. S. 2003. Intra-mitochondrial poly-ADP-ribosylation contributes to NAD+ depletion and cell death induced by oxidative stress. J. Biol. Chem. Mar 7 (epub ahead of print).

  75. van Loo, G., Schotte, P., van Gurp, M., Demol, H., Hoorelbeke, B., Gevaert, K., Rodriguez, I., Ruiz Carrillo, A., Vandekerekhove, J., Declereq, W., Boyaert, R., and Vandenabeele, P. 2001. Endonuclease G: A mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation. Cell. Death Differ. 8:1136–1142.

    PubMed  Google Scholar 

  76. Shibata, M., Hattori, H., Sasaki, T., Gotoh, J., Hamada, J., and Fukuuchi, Y. 2002. Subcellular localization of a promoter and an inhibitor of apoptosis (Smac/DIABLO and XIAP) during brain ischemia/reperfusion. Neuroreport 13:1985–1988.

    PubMed  Google Scholar 

  77. Troy, C. M., Friedman, J. E., and Friedman, W. J. 2002. Mechanisms of p75-mediated death of hippocampal neurons: Role of caspases. J. Biol. Chem. 277:34295–342302.

    PubMed  Google Scholar 

  78. Suzuki, Y., Imai, Y., Nakayama, H., Takahashi, K., Takio, K., and Takahashi, R. 2001. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol. Cells 8:613–621.

    Google Scholar 

  79. Wang, X., Yang, C., Chai, J., Shi, Y., and Xue, D. 2002. Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans. Science 298:1587–1592.

    PubMed  Google Scholar 

  80. Deshmuckh, M. and Johnson E. M. Jr. 1998. Evidence of a novel event during neuronal death: Development of competence-to-die in response to cytoplasmic cytochrome c. Neuron 21:6?

    Google Scholar 

  81. Deshmukh, M., Du, C., Wang, X., and Johnson, E. M. Jr. 2002. Exogenous Smac induces competence and permits caspase activation in sympathetic neurons. J. Neurosci. 22:8018–8027.

    PubMed  Google Scholar 

  82. Haraguchi, M., Torii, S., Matsuzawa, S., Xie, Z., Kitada, S., Krajewski, S., Yoshida, H., Mak, T. W., and Reed, J. C. 2000. Apoptotic protease activating factor 1 (Apaf-1)-independent cell death suppression by Bcl-2. J. Exp. Med. 191:1709–1720.

    PubMed  Google Scholar 

  83. Marsden, V. S., O'Connor, L., O'Reilly, L. A., Silke, J., Metcalf, D., Ekert, P. G., Huang, D. C., Cecconi, F., Kuida, K., Tomaselli, K. J., Roy, S., Nicholson, D. W., Vaux, D. L., Bouillet, P., Adams, J. M., and Strassor, A. 2002. Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome. Nature 419:634–637.

    PubMed  Google Scholar 

  84. Liu, X., Zou, H., Slaughter, C., and Wang, X. 1997. DFF: A heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 89:175–184.

    PubMed  Google Scholar 

  85. Didenko, V. V., Ngo, H., Minchew, C. L., Boudreaux, D. J., Widmayer, M. A., and Baskin, D. S. 2002. Caspase-3-dependent and-independent apoptosis in focal brain ischemia. Mol. Med. 8:347–352.

    PubMed  Google Scholar 

  86. Viswanath, V., Wu, Y., Boonplueang, R., Chen, S., Stevenson, F. F., Yantiri, F., Yang, L., Beal, M. F., and Andersen, J. K. 2001. Caspase-9 activation results in downstream caspase-8 activation and bid cleavage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease. J. Neurosci. 21:9519–9528.

    PubMed  Google Scholar 

  87. McGinnis, K. M., Gnegy, M. E., and Wang, K. K. 1999. Endogenous bax translocation in SH-SY5Y human neuroblastoma cells and cerebellar granule neurons undergoing apoptosis. J. Neurochem. 72:1899–1906.

    PubMed  Google Scholar 

  88. Putcha, G. V., Harris, C. A., Moulder, K. L., Easton, R. M., Thompson, C. B., and Johnson, E. M. Jr. 2002. Intrinsic and extrinsic pathway signaling during neuronal apoptosis: Lessons from the analysis of mutant mice. J. Cell. Biol. 157:441–453.

    PubMed  Google Scholar 

  89. Epand, R. F., Martinou, J. C., Montessuit, S., and Epand, R. M. 2002. Membrane perturbations induced by the apoptotic Bax protein. Biochem. J. 367:849–855.

    PubMed  Google Scholar 

  90. Roucou, X., Rostovtseva, T., Montessuit, S., Martinou, J. C., and Antonsson, B. 2002. Bid induces cytochrome c-impermeable Bax channels in liposomes. Biochem. J. 363:547–552.

    PubMed  Google Scholar 

  91. Kuwana, T., Mackey, M. R., Perkins, G., Ellisman, M. H., Latterich, M., Schneiter, R., Green, D. R., and Newmeyer, D. D. 2002. Bid, bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111:331–342.

    PubMed  Google Scholar 

  92. Zoratti, M. and Szabo, I. 1995. The mitochondrial permeability transition. Biochim. Biophys. Acta 1241:139–176.

    PubMed  Google Scholar 

  93. Hunter, D. R., Haworth, R. A., and Southard, J. H. 1976. Relationship between configuration, function, and permeability in calcium-treated mitochondria. J. Biol. Chem. 251:5069–5077.

    PubMed  Google Scholar 

  94. Andreyev, A. and Fiskum, G. 1999. Calcium induced release of mitochondrial cytochrome c by different mechanisms selective for brain versus liver. Cell. Death Differ. 6:825–832.

    PubMed  Google Scholar 

  95. Schild, L., Keilhoff, G., Augustin, W., Reiser, G., and Striggow F. 2001. Distinct Ca2+ thresholds determine cytochrome c release or permeability transition pore opening in brain mitochondria. FASEB J. 80:565–567.

    Google Scholar 

  96. Hortelano, S., Dallaporta, B., Zamzami, N., Hirsch, T., Susin, S. A., Marzo, I., Bosca, L., and Kroemer, G. 1997. Nitric oxide induces apoptosis via triggering mitochondrial permeability transition. FEBS Lett. 410:373–377.

    PubMed  Google Scholar 

  97. Lemasters, J. J., Nieminen, A. L., Qian, T., Trost, L. C., Elmore, S. P., Nishimura, Y., Crowe, R. A., Cascio, W. E., Bradham, C. A., Brenner, D. A., and Herman, B. 1998. The mitochondrial permeability transition in cell death: A common mechanism in necrosis, apoptosis and autophagy. Biochim. Biophys. Acta 1366:177–196.

    PubMed  Google Scholar 

  98. Marzo, I., Brenner, C., Zamzami, N., Susin, S. A., Beutner, G., Brdiczka, D., Remy, R., Xie, Z. H., Reed, J. C., and Kroemer, G. 1998. The permeability transition pore complex: A target for apoptosis regulation by caspases and bcl-2-related proteins. J. Exp. Med. 187:1261–1271.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  100. Heiskanen, K. M., Bhat, M. B., Wang, H. W., Ma, J., and Nieminen, A. L. 1999. Mitochondrial depolarization accompanies cytochrome c release during apoptosis in PC6 cells. J. Biol. Chem. 274:5654–5658.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  102. Goldstein, J. C., Waterhouse, N. J., Juin, P., Evan, G. I., and Green, D. R. 2000. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat. Cell Biol. 2:156–162.

    PubMed  Google Scholar 

  103. Zhuang, J., Dinsdale, D., and Cohen, G. M. 1998. Apoptosis, in human monocytic THP.1 cells, results in the release of cytochrome c from mitochondria prior to their ultracondensation, formation of outer membrane discontinuities and reduction in inner membrane potential. Cell. Death Differ. 5:953–962.

    PubMed  Google Scholar 

  104. Stefanis, L., Park, D. S., Friedman, W. J., and Greene, L. A. Caspase-dependent and-independent death of camptothecin-treated embryonic cortical neurons. J. Neurosci. 19:6235–6247.

  105. Krohn, A. J., Wahlbrink, T., and Prehn, J. H. Mitochondrial depolarization is not required for neuronal apoptosis. J. Neurosci. 19:7394–7404.

  106. Brustovetsky, N., Brustovetsky, T., Jemmerson, R., and Dubinsky, J. M. 2002. Calcium-induced cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane. J. Neurochem. 80:207–218.

    PubMed  Google Scholar 

  107. Marzo, I., Brenner, C., Zamzami, N., Jurgensmeier, J. M., Susin, S. A., Vieira, H. L., Prevost, M. C., Xie, Z., Matsuyama, S., Reed, J. C., and Kroemer, G. 1998. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281:2027–2031.

    PubMed  Google Scholar 

  108. Arnoult, D., Parone, P., Martinou, J. C., Antonsson, B., Estaquier, J., and Ameisen, J. C. 2002. Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli. J. Cell Biol. 159:923–929.

    PubMed  Google Scholar 

  109. Dussmann, H., Kogel, D., Rehm, M., and Prehn, J. H. 2003. Mitochondrial membrane permeabilization and superoxide production during apoptosis: A single-cell analysis. J. Biol. Chem. 278:12645–12649.

    PubMed  Google Scholar 

  110. Murphy, B. M., O'Neill, A. J., Adrain, C., Watson, R. W., and Martin, S. J. 2003. The apoptosome pathway to caspase activation in primary human neutrophils exhibits dramatically reduced requirements for cytochrome C. J. Exp. Med. 197:625–632.

    PubMed  Google Scholar 

  111. Mootha, V. K., Wei, M. C., Buttle, K. F., Scorrano, L., Panoutsakopoulou, V., Mannella, C. A., and Korsmeyer, S. J. 2001. A reversible component of mitochondrial respiratory dysfunction in apoptosis can be rescued by exogenous cytochrome c. EMBO J. 20:661–671.

    PubMed  Google Scholar 

  112. Waterhouse, N. J., Goldstein, J. C., von Ahsen, O., Schuler, M., Newmeyer, D. D., and Green, D. R. 2001. Cytochrome c maintains mitochondrial transmembrane potential and ATP generation after outer mitochondrial membrane permeabilization during the apoptotic process. J. Cell Biol. 153:319–328.

    PubMed  Google Scholar 

  113. Glazner, G. W., Chan, S. L., Lu, C., and Mattson, M. P. 2000. Caspase-mediated degradation of AMPA receptor subunits: A mechanism for preventing excitotoxic necrosis and ensuring apoptosis. J. Neurosci. 20:3641–3649.

    PubMed  Google Scholar 

  114. Davey, G. P., Peuchen, S., and Clark, J. B. 1998. Energy thresholds in brain mitochondria: Potential involvement in neurodegeneration. J. Biol. Chem. 80:12753–12757.

    Google Scholar 

  115. D'Herde, K., De Prest, B., Mussche, S., Schotte, P., Beyaert, R., Coster, R. V., and Roels, F. 2000. Ultrastructural localization of cytochrome c in apoptosis demonstrates mitochondrial heterogeneity. Cell Death Differ. 7:331–337.

    PubMed  Google Scholar 

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  1. Department of Bioscience, AstraZeneca R&D, S-151 85, Södertälje, Sweden

    Samantha L. Budd Haeberlein

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Haeberlein, S.L.B. Mitochondrial Function in Apoptotic Neuronal Cell Death. Neurochem Res 29, 521–530 (2004). https://doi.org/10.1023/B:NERE.0000014823.74782.b7

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