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Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis?

Nature Cell Biology volume 1, pages E209–E216 (1999)Cite this article

Abstract

Programmed cell death (apoptosis) is used by multicellular organisms during development and to maintain homeostasis within mature tissues. One of the first genes shown to regulate apoptosis was bcl-2. Subsequently, a number of Bcl-2-related proteins have been identified. Despite overwhelming evidence that Bcl-2 proteins are evolutionarily conserved regulators of apoptosis, their precise biochemical function remains controversial. Three biochemical properties of Bcl-2 proteins have been identified: their ability to localize constitutively and/or inducibly to the outer mitochondrial, outer nuclear and endoplasmic reticular membranes, their ability to form heterodimers with proteins bearing an amphipathic helical BH3 domain, and their ability to form ion-conducting channels in synthetic membranes. The discovery that mitochondria can play a key part in the induction of apoptosis has focused attention on the role that Bcl-2 proteins may have in regulating either mitochondrial physiology or mitochondria-dependent caspase activation. Here we attempt to synthesize our current understanding of the part played by mitochondria in apoptosis with a consideration of how Bcl-2 proteins might control cell death through an ability to regulate mitochondrial physiology.

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Figure 1: Mitochondria-dependent caspase activation.
Figure 2: Proposed mechanisms to account for cytochrome c redistribution during apoptosis.
Figure 3: Proposed functions for the ANT and the VDAC in formation of the permeability-transition pore and in oxidative phosphorylation.
Figure 4: Possible consequences for cell survival following mitochondrial damage.

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References

  1. Newmeyer, D. D., Farschon, D. M. & Reed, J. C. 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).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Thornberry N. A. & Lazebnik, Y. Caspases: enemies within. Science 281, 1312–1316 (1998).

    CAS  PubMed  Google Scholar 

  4. Zou, H., Henzel, W. J., 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).

    CAS  PubMed  Google Scholar 

  5. Li, P. et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479–489 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Saleh, A., Srinivasula, S. M., Acharya, S., Fishel, R. & Alnemri, E. S. Cytochrome c and dATP-mediated oligomerization of Apaf-1 is a prerequisite for procaspase-9 activation. J. Biol. Chem. 274, 17941–17945 (1999).

    CAS  PubMed  Google Scholar 

  8. 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).

    CAS  PubMed  Google Scholar 

  9. Slee, E. A. et al. Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J. Cell Biol. 144, 281–292 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Mayer, A., Neupert, W. & Lill, R. Translocation of apocytochrome c across the outer membrane of mitochondria. J. Biol. Chem. 270, 12390–12397 (1995).

    CAS  PubMed  Google Scholar 

  11. Kluck, R. M. et al. Cytochrome c activation of CPP32-like proteolysis plays a critical role in a Xenopus cell-free apoptosis system. EMBO J. 16, 4639–4649 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Susin, S. A. et al. Mitochondrial release of caspase-2 and -9 during the apoptotic process. J. Exp. Med. 189, 381–394 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Mancini, M. et al. The caspase-3 precursor has a cytosolic and mitochondrial distribution: implications for apoptotic signaling. J. Cell Biol. 140, 1485–1495 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Samali, A., Zhivotovsky, B., Jones, D. P. & Orrenius, S. Detection of pro-caspase-3 in cytosol and mitochondria of various tissues. FEBS Lett. 431, 167–169 (1998).

    CAS  PubMed  Google Scholar 

  15. Samali, A., Cai, J., Zhivotovsky, B., Jones, D. P. & 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Krajewski, S. et al. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc. Natl Acad. Sci. USA 96, 5752–5757 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Susin, S. A. et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397, 441–446 (1999).

    CAS  PubMed  Google Scholar 

  18. Kluck, R. M., Bossy-Wetzel, E., Green, D. R. & Newmeyer, D. D. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275, 1132–1136 (1997).

    CAS  PubMed  Google Scholar 

  19. Yang, J. et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275, 1129–1132 (1997).

    CAS  PubMed  Google Scholar 

  20. Vander Heiden, M. G., Chandel, N. S., Williamson, E. K., Schumacker, P. T. & Thompson, C. B. Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell 91, 627–637 (1997).

    CAS  PubMed  Google Scholar 

  21. Bossy-Wetzel, E., Newmeyer, D. D. & Green, D. R. 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).

    CAS  PubMed  Google Scholar 

  22. Manon, S., Chaudhuri, B. & Guerin, M. Release of cytochrome c and decrease of cytochrome c oxidase in Bax-expressing yeast cells, and prevention of these effects by coexpression of Bcl-xL. FEBS Lett. 415, 29–32 (1997).

    CAS  PubMed  Google Scholar 

  23. Rosse, T. et al. Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature 391, 496–499 (1998).

    CAS  PubMed  Google Scholar 

  24. Jurgensmeier, J. M. et al. Bax directly induces release of cytochrome c from isolated mitochondria. Proc. Natl Acad. Sci. USA 95, 4997–5002 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Pastorino, J. G., Chen, S. T., Tafani, M., Snyder, J. W. & Farber, J. L. The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J. Biol. Chem. 273, 7770–7775 (1998).

    CAS  PubMed  Google Scholar 

  26. Vander Heiden, M. G., Chandel, N. S., Schumacker, P. T. & Thompson, C. B. Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. Mol. Cell 3, 159–167 (1999).

    CAS  PubMed  Google Scholar 

  27. Hockenbery, D. M., Oltvai, Z. N., Yin, X. M., Milliman, C. L. & Korsmeyer, S. J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75, 241–251 (1993).

    CAS  PubMed  Google Scholar 

  28. Kane, D. J. et al. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science 262, 1274–1277 (1993).

    CAS  PubMed  Google Scholar 

  29. Gottlieb, R. A., Nordberg, J., Skowronski, E. & Babior, B. M. Apoptosis induced in Jurkat cells by several agents is preceded by intracellular acidification. Proc. Natl Acad. Sci. USA 93, 654–658 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zamzami, N. et al. Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J. Exp. Med. 182, 367–377 (1995).

    CAS  PubMed  Google Scholar 

  31. Shimizu, S. et al. Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux. Proc. Natl Acad. Sci. USA 95, 1455–1459 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Nguyen, M., Millar, D. G., Yong, V. W., Korsmeyer, S. J. & Shore, G. C. Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence. J. Biol. Chem. 268, 25265–25268 (1993).

    CAS  PubMed  Google Scholar 

  33. Krajewski, S. et al. 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).

    CAS  PubMed  Google Scholar 

  34. Tanaka, S., Saito, K. & Reed, J. C. Structure-function analysis of the Bcl-2 oncoprotein. Addition of a heterologous transmembrane domain to portions of the Bcl-2 beta protein restores function as a regulator of cell survival. J. Biol. Chem. 268, 10920–10926 (1993).

    CAS  PubMed  Google Scholar 

  35. Nguyen, M. et al. Role of membrane anchor domain of Bcl-2 in suppression of apoptosis caused by E1B-defective adenovirus. J. Biol. Chem. 269, 16521–16524 (1994).

    CAS  PubMed  Google Scholar 

  36. Wolter, K. G. et al. Movement of Bax from the cytosol to mitochondria during apoptosis. J. Cell Biol. 139, 1281–1292 (1997).

    CAS  PubMed  Google Scholar 

  37. Hsu, Y. T., Wolter, K. G. & Youle, R. J. Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis. Proc. Natl Acad. Sci. USA 94, 3668–3672 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Gross, A., Jockel, J., Wei, M. C. & Korsmeyer, S. J. Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J. 17, 3878–3885 (1998).

    CAS  PubMed  Google Scholar 

  39. Cheng, E. H., Levine, B., Boise, L. H., Thompson, C. B. & Hardwick, J. M. Bax-independent inhibition of apoptosis by Bcl-XL. Nature 379, 554–556 (1996).

    CAS  PubMed  Google Scholar 

  40. Minn, A. J. et al. Bcl-xL regulates apoptosis by heterodimerization-dependent and -independent mechanisms. EMBO J. 18, 632–643 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Chinnaiyan, A. M., O’Rourke, K., Lane, B. R. & Dixit, V. M. Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death. Science 275, 1122–1126 (1997).

    CAS  PubMed  Google Scholar 

  42. Spector, M. S., Desnoyers, S., Hoeppner, D. J. & Hengartner, M. O. Interaction between the C. elegans cell-death regulators CED-9 and CED-4. Nature 385, 653–656 (1997).

    CAS  PubMed  Google Scholar 

  43. Wu, D., Wallen, H. D. & Nunez, G. Interaction and regulation of subcellular localization of CED-4 by CED-9. Science 275, 1126–1129 (1997).

    CAS  PubMed  Google Scholar 

  44. Pan, G., O’Rourke, K. & Dixit, V. M. Caspase-9, Bcl-xL, and Apaf-1 form a ternary complex. J. Biol. Chem. 273, 5841 (1998).

    CAS  PubMed  Google Scholar 

  45. Hu, Y., Benedict, M. A., Wu, D., Inohara, N. & Nunez, G. Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proc. Natl Acad. Sci. USA 95, 4386–4391 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Moriishi, K., Huang, D. C., Cory, S. & Adams, J. M. Bcl-2 family members do not inhibit apoptosis by binding the caspase activator Apaf-1. Proc. Natl Acad. Sci. USA 96, 9683–9688 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Chang, B. S., Minn, A. J., Muchmore, S. W., Fesik, S. W. & Thompson, C. B. Identification of a novel regulatory domain in Bcl-xL and Bcl-2. EMBO J. 16, 968–977 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Muchmore, S. W. et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 381, 335–341 (1996).

    CAS  PubMed  Google Scholar 

  49. Minn, A. J. et al. Bcl-x(L) forms an ion channel in synthetic lipid membranes. Nature 385, 353–357 (1997).

    CAS  PubMed  Google Scholar 

  50. Schendel, S. L. et al. Channel formation by antiapoptotic protein Bcl-2. Proc. Natl Acad. Sci. USA 94, 5113–5118 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Antonsson, B. et al. Inhibition of Bax channel-forming activity by Bcl-2. Science 277, 370–372 (1997).

    CAS  PubMed  Google Scholar 

  52. Schendel, S. L. et al. Ion channel activity of the BH3 only Bcl-2 family member, BID. J. Biol. Chem. 274, 21932–21936 (1999).

    CAS  PubMed  Google Scholar 

  53. Matsuyama, S., Schendel, S. L., Xie, Z. & Reed, J. C. Cytoprotection by Bcl-2 requires the pore-forming alpha5 and alpha6 helices. J. Biol. Chem. 273, 30995–31001 (1998).

    CAS  PubMed  Google Scholar 

  54. 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).

    CAS  PubMed  Google Scholar 

  55. Zamzami, N., Brenner, C., Marzo, I., Susin, S. A. & Kroemer, G. Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins. Oncogene 16, 2265–2282 (1998).

    CAS  PubMed  Google Scholar 

  56. Basanez, G. et al. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Cosulich, S. C., Worall, V., Hedge, P. J., Green, S. & Clarke, P. R. Regulation of apoptosis by BH3 domains in a cell-free system. Curr. Biol. 7, 913–920 (1997).

    CAS  PubMed  Google Scholar 

  58. Pattus, F., Heitz, F., Martinez, C., Provencher, S. W. & Lazdunski, C. Secondary structure of the pore-forming colicin A and its C-terminal fragment. Experimental fact and structure prediction. Eur. J. Biochem. 152, 681–689 (1985).

    CAS  PubMed  Google Scholar 

  59. Single, B., Leist, M. & Nicotera, P. Simultaneous release of adenylate kinase and cytochrome c in cell death. Cell Death Differ. 5, 1001–1003 (1998).

    CAS  PubMed  Google Scholar 

  60. Kohler, C. et al. Release of adenylate kinase 2 from the mitochondrial intermembrane space during apoptosis. FEBS Lett. 447, 10–12 (1999).

    CAS  PubMed  Google Scholar 

  61. Priault, M., Chaudhuri, B., Clow, A., Camougrand, N. & Manon, S. Investigation of bax-induced release of cytochrome c from yeast mitochondria: permeability of mitochondrial membranes, role of VDAC and ATP requirement. Eur. J. Biochem. 260, 684–691 (1999).

    CAS  PubMed  Google Scholar 

  62. Green, D. & Kroemer, G. The central executioners of apoptosis: caspases or mitochondria? Trends Cell Biol. 8, 267–271 (1998).

    CAS  PubMed  Google Scholar 

  63. Zoratti, M. & Szabo, I. The mitochondrial permeability transition. Biochim. Biophys. Acta 1241, 139–176 (1995).

    PubMed  Google Scholar 

  64. Zamzami, N. et al. Mitochondrial control of nuclear apoptosis. J. Exp. Med. 183, 1533–1544 (1996).

    CAS  PubMed  Google Scholar 

  65. Scorrano, L., Petronilli, V., Di Lisa, F. & Bernardi, P. Commitment to apoptosis by GD3 ganglioside depends on opening of the mitochondrial permeability transition pore. J. Biol. Chem. 274, 22581–22585 (1999).

    CAS  PubMed  Google Scholar 

  66. Kristal, B. S. & Brown, A. M. Apoptogenic ganglioside GD3 directly induces the mitochondrial permeability transition. J. Biol. Chem. 274, 23169–23175 (1999).

    CAS  PubMed  Google Scholar 

  67. Zamzami, N. et al. Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potential during apoptosis. FEBS Lett. 384, 53–57 (1996).

    CAS  PubMed  Google Scholar 

  68. Eskes, R. et al. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Petronilli, V. et al. Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence. Biophys. J. 76, 725–734 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Minamikawa, T., Williams, D. A., Bowser, D. N. & Nagley, P. Mitochondrial permeability transition and swelling can occur reversibly without inducing cell death in intact human cells. Exp. Cell Res. 246, 26–37 (1999).

    CAS  PubMed  Google Scholar 

  71. Kerr, P. M., Suleiman, M. S. & Halestrap, A. P. Reversal of permeability transition during recovery of hearts from ischemia and its enhancement by pyruvate. Am. J. Physiol. 276, H496–H502 (1999).

    CAS  PubMed  Google Scholar 

  72. Ichas, F. & Mazat, J. P. From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high-conductance state. Biochim. Biophys. Acta 1366, 33–50 (1998).

    CAS  PubMed  Google Scholar 

  73. Bradham, C. A. et al. The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release. Mol. Cell. Biol. 18, 6353–6364 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Brdiczka, D., Beutner, G., Ruck, A., Dolder, M. & Wallimann, T. The molecular structure of mitochondrial contact sites. Their role in regulation of energy metabolism and permeability transition. Biofactors 8, 235–242 (1998).

    CAS  PubMed  Google Scholar 

  76. Wyss, M., Smeitink, J., Wevers, R. A. & Wallimann, T. Mitochondrial creatine kinase: a key enzyme of aerobic energy metabolism. Biochim. Biophys. Acta 1102, 119–166 (1992).

    CAS  PubMed  Google Scholar 

  77. Adams, V. et al. Porin interaction with hexokinase and glycerol kinase: metabolic microcompartmentation at the outer mitochondrial membrane. Biochem. Med. Metab. Biol. 45, 271–291 (1991).

    CAS  PubMed  Google Scholar 

  78. Marzo, I. et al. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281, 2027–2031 (1998).

    CAS  PubMed  Google Scholar 

  79. Marzo, I. et al. The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins. J. Exp. Med. 187, 1261–1271 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Narita, M. et al. Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc. Natl Acad. Sci. USA 95, 14681–14686 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Hackenbrock, C. R. Ultrastructural bases for metabolically linked mechanical activity in mitochondria. I. Reversible ultrastructural changes with change in metabolic steady state in isolated liver mitochondria. J. Cell Biol. 30, 269–297 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Banki, K., Hutter, E., Gonchoroff, N. J. & Perl, A. Elevation of mitochondrial transmembrane potential and reactive oxygen intermediate levels are early events and occur independently from activation of caspases in Fas signaling. J. Immunol. 162, 1466–1479 (1999).

    CAS  PubMed  Google Scholar 

  83. Kennedy, S. G., Kandel, E. S., Cross, T. K. & Hay, N. Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol. Cell. Biol. 19, 5800–5810 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Bernardi, P. Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol. Rev. 79, 1127–1155 (1999).

    CAS  PubMed  Google Scholar 

  85. Halestrap, A. P. The regulation of the matrix volume of mammalian mitochondria in vivo and in vitro and its role in the control of mitochondrial metabolism. Biochim. Biophys. Acta 973, 355–382 (1989).

    CAS  PubMed  Google Scholar 

  86. Rostovtseva, T. & Colombini, M. VDAC channels mediate and gate the flow of ATP: implications for the regulation of mitochondrial function. Biophys. J. 72, 1954–1962 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Hodge, T. & Colombini, M. Regulation of metabolite flux through voltage-gating of VDAC channels. J. Membr. Biol. 157, 271–279 (1997).

    CAS  PubMed  Google Scholar 

  88. Vaux, D. L., Cory, S. & Adams, J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335, 440–442 (1988).

    CAS  PubMed  Google Scholar 

  89. Decker, R. S. & Wildenthal, K. Lysosomal alterations in hypoxic and reoxygenated hearts. I. Ultrastructural and cytochemical changes. Am. J. Pathol. 98, 425–444 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Shimizu, S. et al. Bcl-2 blocks loss of mitochondrial membrane potential while ICE inhibitors act at a different step during inhibition of death induced by respiratory chain inhibitors. Oncogene 13, 21–29 (1996).

    CAS  PubMed  Google Scholar 

  91. McCarthy, N. J., Whyte, M. K., Gilbert, C. S. & Evan, G. I. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Amarante-Mendes, G. P. et al. Anti-apoptotic oncogenes prevent caspase-dependent and independent commitment for cell death. Cell Death Differ. 5, 298–306 (1998).

    CAS  PubMed  Google Scholar 

  93. Soengas, M. S. et al. Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science 284, 156–159 (1999).

    CAS  PubMed  Google Scholar 

  94. Deshmukh, M. & Johnson, E. M. Jr Evidence of a novel event during neuronal death: development of competence-to-die in response to cytoplasmic cytochrome c. Neuron 21, 695–705 (1998).

    CAS  PubMed  Google Scholar 

  95. Martinou, I. et al. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Deveraux, Q. L. et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17, 2215–2223 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Tang, D. G., Chen, Y. Q. & Honn, K. V. Arachidonate lipoxygenases as essential regulators of cell survival and apoptosis. Proc. Natl Acad. Sci. USA 93, 5241–5246 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. van Leyen, K., Duvoisin, R. M., Engelhardt, H. & Wiedmann, M. A function for lipoxygenase in programmed organelle degradation. Nature 395, 392–395 (1998).

    CAS  PubMed  Google Scholar 

  99. Eguchi, Y., Shimizu, S. & Tsujimoto, Y. Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res. 57, 1835–1840 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  101. Zhu, W. et al. Bcl-2 mutants with restricted subcellular location reveal spatially distinct pathways for apoptosis in different cell types. EMBO J. 15, 4130–4141 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank members of the Thompson laboratory for their critique of the manuscript and S. Kerns for expert editorial assistance.

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  1. Committee on Immunology, University of Chicago, Chicago, 60637, Illinois, USA

    Matthew G. Vander Heiden

  2. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Matthew G. Vander Heiden & Craig B. Thompson

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Correspondence to Craig B. Thompson.

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Vander Heiden, M., Thompson, C. Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis?. Nat Cell Biol 1, E209–E216 (1999). https://doi.org/10.1038/70237

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