Programmed Necrosis: A “New” Cell Death Outcome for Injured Adult Neurons?

  • Slavica Krantic
  • Santos A. Susin


Historically, cell death has been divided into two generic categories: apoptosis, which requires energy and in which the cell plays an active role, and necrosis, which occurs accidentally, does not require energy consumption and is considered as a passive, uncontrolled cell death program. Among the conceptually opposite cell death forms, apoptosis is the best understood. This death program has been defined as developmentally programmed and ordered cellular response. Apoptosis is initiated by cell rounding and subsequent detachment from the surrounding cells. Chromatin condenses into “crescent-like” forms abutting the inner nuclear membrane. Plasma membrane convolutes and gives rise to characteristic vesicles containing cellular organelles and cytoplasm, known as the “apoptotic bodies.” Apoptosis is generally not accompanied by inflammation since macrophages or neighbouring cells engulf the formed apoptotic bodies before the loss of plasma membrane integrity (Kerr et al. 1972). In contrast to apoptosis, necrosis is characterized by disruption of the plasma membrane with a subsequent water influx and leakage of cell content to the surroundings. Cell death by necrosis can elicit an inflammatory response (Edinger and Thompson 2004).


Calpain Activation Genetic Ablation Mitochondrial Outer Membrane Permeabilization Excitotoxic Cell Death Excitotoxic Neuronal Death 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We apologize to colleagues whose original work we could not cite owing to limitations of space. The authors wish to thank Marcela Segade for invaluable help. Our research is supported by institutional grants from Institut Pasteur and CNRS and by specific grants from Ligue Contre le Cancer and Association pour la Recherche sur le Cancer (ARC; contract n° 4043) to Santos A. Susin and joint INSERM/FRSQ cooperation programme to Slavica Krantic (France) and Remi Quirion (Canada).


  1. Aarts M, Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W, MacDonald JF, Tymianski M (2003) A key role for TRPM7 channels in anoxic neuronal death. Cell 115:863–877PubMedGoogle Scholar
  2. Adhami F, Schloemer A, Kuan CY (2007) The roles of autophagy in cerebral ischemia. Autophagy 3:42–44PubMedGoogle Scholar
  3. Alford S, Frenguelli BG, Schofield JG, Collingridge GL (1993) Characterization of Ca2+ signals induced in hippocampal CA1 neurones by the synaptic activation of NMDA receptors. J Physiol 469:693–716PubMedGoogle Scholar
  4. Amadoro G, Ciotti MT, Costanzi M, Cestari V, Calissano P, Canu N (2006) NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation. Proc Natl Acad Sci USA 103:2892–2897PubMedGoogle Scholar
  5. Andrabi SA et al (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci USA 103:18308–18313PubMedGoogle Scholar
  6. Andreyev AY, Fahy B, Fiskum G (1998) Cytochrome c release from brain mitochondria is independent of the mitochondrial permeability transition. FEBS Lett 439:373–376PubMedGoogle Scholar
  7. Araujo IM et al (2005) Proteolysis of NR2B by calpain in the hippocampus of epileptic rats. Neuroreport 16:393–396PubMedGoogle Scholar
  8. Baggetto LG (1992) Deviant energetic metabolism of glycolytic cancer cells. Biochimie 74:959–974PubMedGoogle Scholar
  9. Baines CP et al (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662PubMedGoogle Scholar
  10. Bajt ML, Cover C, Lemasters JJ, Jaeschke H (2006) Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Toxicol Sci 94:217–225PubMedGoogle Scholar
  11. Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120:483–495PubMedGoogle Scholar
  12. Bano D et al (2005) Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell 120:275–285PubMedGoogle Scholar
  13. Barkla DH, Gibson PR (1999) The fate of epithelial cells in the human large intestine. Pathology 31:230–238PubMedGoogle Scholar
  14. Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P (2005) Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem 280:18558–18561PubMedGoogle Scholar
  15. Bauer DE, Harris MH, Plas DR, Lum JJ, Hammerman PS, Rathmell JC, Riley JL, Thompson CB (2004) Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds proliferative demand. FASEB J 18:1303–1305PubMedGoogle Scholar
  16. Beaulaton J, Lockshin RA (1982) The relation of programmed cell death to development and reproduction: Comparative studies and an attempt at classification. Int Rev Cytol 79:215–235PubMedGoogle Scholar
  17. Ben-Ari Y (2001) Cell death and synaptic reorganizations produced by seizures. Epilepsia 42(Suppl 3):5–7PubMedGoogle Scholar
  18. Berger NA, Sims JL, Catino DM, Berger SJ (1983) Poly(ADP-ribose) polymerase mediates the suicide response to massive DNA damage: studies in normal and DNA-repair defective cells. Princess Takamatsu Symp 13:219–226PubMedGoogle Scholar
  19. Boise LH, Collins CM (2001) Salmonella-induced cell death: Apoptosis, necrosis or programmed cell death? Trends Microbiol 9:64–67PubMedGoogle Scholar
  20. Borst P, Rottenberg S (2004) Cancer cell death by programmed necrosis? Drug Resist Update 7:321–324Google Scholar
  21. Bose I, Ghosh B (2007) The p53-MDM2 network: From oscillations to apoptosis. J Biosci 32:991–997PubMedGoogle Scholar
  22. Boujrad H, Gubkina O, Robert N, Krantic S, Susin SA (2007) AIF-mediated programmed necrosis: A highly regulated way to die. Cell Cycle 6:2612–2619PubMedGoogle Scholar
  23. Bras M et al (2007) Drp1 mediates caspase-independent type III cell death in normal and leukemic cells. Mol Cell Biol 27:7073–7088PubMedGoogle Scholar
  24. Bredesen DE (2007) Key note lecture: Toward a mechanistic taxonomy for cell death programs. Stroke 38:652–660PubMedGoogle Scholar
  25. Broker LE, Kruyt FA, Giaccone G (2005) Cell death independent of caspases: A review. Clin Cancer Res 11:3155–3162PubMedGoogle Scholar
  26. Budd SL, Nicholls DG (1996) Mitochondria, calcium regulation, and acute glutamate excitotoxicity in cultured cerebellar granule cells. J Neurochem 67:2282–2291PubMedGoogle Scholar
  27. Camacho A, Massieu L (2006) Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death. Arch Med Res 37:11–18PubMedGoogle Scholar
  28. Cande C et al (2004) AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis. Oncogene 23:1514–1521PubMedGoogle Scholar
  29. Cao X, Deng X, May WS (2003a) Cleavage of Bax to p18 Bax accelerates stress-induced apoptosis, and a cathepsin-like protease may rapidly degrade p18 Bax. Blood 102:2605–2614PubMedGoogle Scholar
  30. Cao G, Clark RS, Pei W, Yin W, Zhang F, Sun FY, Graham SH, Chen J (2003b) Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation. J Cereb Blood Flow Metab 23:1137–1150PubMedGoogle Scholar
  31. Cao G et al (2007) Critical role of calpain I in mitochondrial release of apoptosis-inducing factor in ischemic neuronal injury. J Neurosci 27:9278–9293PubMedGoogle Scholar
  32. Cartron PF, Oliver L, Juin P, Meflah K, Vallette FM (2004) The p18 truncated form of Bax behaves like a Bcl-2 homology domain 3-only protein. J Biol Chem 279:11503–11512PubMedGoogle Scholar
  33. Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A (2006) Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9:351–365PubMedGoogle Scholar
  34. Chautan M, Chazal G, Cecconi F, Gruss P, Golstein P (1999) Interdigital cell death can occur through a necrotic and caspase-independent pathway. Curr Biol 9:967–970PubMedGoogle Scholar
  35. Chen J, Liu X, Mandel LJ, Schnellmann RG (2001a) Progressive disruption of the plasma membrane during renal proximal tubule cellular injury. Toxicol Appl Pharmacol 171:1–11PubMedGoogle Scholar
  36. Chen M, He H, Zhan S, Krajewski S, Reed JC, Gottlieb RA (2001b) Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/reperfusion. J Biol Chem 276:30724–30728PubMedGoogle Scholar
  37. Cheung EC et al (2005) Apoptosis-inducing factor is a key factor in neuronal cell death propagated by BAX-dependent and BAX-independent mechanisms. J Neurosci 25:1324–1334PubMedGoogle Scholar
  38. Chihab R, Oillet J, Bossenmeyer C, Daval JL (1998) Glutamate triggers cell death specifically in mature central neurons through a necrotic process. Mol Genet Metab 63:142–147PubMedGoogle Scholar
  39. Chua BT, Guo K, Li P (2000) Direct cleavage by the calcium-activated protease calpain can lead to inactivation of caspases. J Biol Chem 275:5131–5135PubMedGoogle Scholar
  40. Clarke PG (1990) Developmental cell death: Morphological diversity and multiple mechanisms. Anat Embryol (Berl) 181:195–213Google Scholar
  41. Colbourne F, Sutherland GR, Auer RN (1999) Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia. J Neurosci 19:4200–4210PubMedGoogle Scholar
  42. Cregan SP, Dawson VL, Slack RS (2004) Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 23:2785–2796PubMedGoogle Scholar
  43. Cuerrier D, Moldoveanu T, Davies PL (2005) Determination of peptide substrate specificity for mu-calpain by a peptide library-based approach: The importance of primed side interactions. J Biol Chem 280:40632–40641PubMedGoogle Scholar
  44. Culmsee C, Zhu C, Landshamer S, Becattini B, Wagner E, Pellecchia M, Blomgren K, Plesnila N (2005) Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci 25:10262–10272PubMedGoogle Scholar
  45. Danial NN, Korsmeyer SJ (2004) Cell death: Critical control points. Cell 116:205–219PubMedGoogle Scholar
  46. Dargusch R, Piasecki D, Tan S, Liu Y, Schubert D (2001) The role of Bax in glutamate-induced nerve cell death. J Neurochem 76:295–301PubMedGoogle Scholar
  47. Daugas E, Nochy D, Ravagnan L, Loeffler M, Susin SA, Zamzami N, Kroemer G (2000) Apoptosis-inducing factor (AIF): A ubiquitous mitochondrial oxidoreductase involved in apoptosis. FEBS Lett 476:118–123PubMedGoogle Scholar
  48. Dawson VL, Dawson TM (2004) Deadly conversations: Nuclear-mitochondrial cross-talk. J Bioenerg Biomembr 36:287–294PubMedGoogle Scholar
  49. Delettre C, Yuste VJ, Moubarak RS, Bras M, Lesbordes-Brion JC, Petres S, Bellalou J, Susin SA (2006a) AIFsh, a novel apoptosis-inducing factor (AIF) pro-apoptotic isoform with potential pathological relevance in human cancer. J Biol Chem 281:6413–6427PubMedGoogle Scholar
  50. Delettre C, Yuste VJ, Moubarak RS, Bras M, Robert N, Susin SA (2006b) Identification and characterization of AIFsh2, a mitochondrial apoptosis-inducing factor (AIF) isoform with nadh oxidase activity. J Biol Chem 281:18507–18518PubMedGoogle Scholar
  51. Donovan N, Becker EB, Konishi Y, Bonni A (2002) JNK phosphorylation and activation of BAD couples the stress-activated signaling pathway to the cell death machinery. J Biol Chem 277:40944–40949PubMedGoogle Scholar
  52. Dubinsky JM, Levi Y (1998) Calcium-induced activation of the mitochondrial permeability transition in hippocampal neurons. J Neurosci Res 53:728–741PubMedGoogle Scholar
  53. Dugan LL, Sensi SL, Canzoniero LM, Handran SD, Rothman SM, Lin TS, Goldberg MP, Choi DW (1995) Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-d-aspartate. J Neurosci 15:6377–6388PubMedGoogle Scholar
  54. Dykens JA (1994) Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated CA2+ and Na+: Implications for neurodegeneration. J Neurochem 63:584–591PubMedGoogle Scholar
  55. Edinger AL, Thompson CB (2004) Death by design: Apoptosis, necrosis and autophagy. Curr Opin Cell Biol 16:663–669PubMedGoogle Scholar
  56. Festjens N, Vanden Berghe T, Vandenabeele P (2006) Necrosis, a well-orchestrated form of cell demise: Signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta 1757:1371–1387PubMedGoogle Scholar
  57. Fonfria E et al (2004) TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP-ribose) polymerase. Br J Pharmacol 143:186–192PubMedGoogle Scholar
  58. Fonnum F, Lock EA (2004) The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: Exemplified with toxic effects on cerebellar granule cells. J Neurochem 88:513–531PubMedGoogle Scholar
  59. Friberg H, Wieloch T (2002) Mitochondrial permeability transition in acute neurodegeneration. Biochimie 84:241–250PubMedGoogle Scholar
  60. Fryer HJ, Knox RJ, Strittmatter SM, Kalb RG (1999) Excitotoxic death of a subset of embryonic rat motor neurons in vitro. J Neurochem 72:500–513PubMedGoogle Scholar
  61. Fujikawa DG, Shinmei SS, Cai B (1999) Lithium-pilocarpine-induced status epilepticus produces necrotic neurons with internucleosomal DNA fragmentation in adult rats. Eur J Neurosci 11:1605–1614PubMedGoogle Scholar
  62. Fujikawa DG, Shinmei SS, Cai B (2000a) Seizure-induced neuronal necrosis: Implications for programmed cell death mechanisms. Epilepsia 41(Suppl 6):S9–S13PubMedGoogle Scholar
  63. Fujikawa DG, Shinmei SS, Cai B (2000b) Kainic acid-induced seizures produce necrotic, not apoptotic, neurons with internucleosomal DNA cleavage: Implications for programmed cell death mechanisms. Neuroscience 98:41–53PubMedGoogle Scholar
  64. Fukuda K, Yamamoto M (1999) Acquisition of resistance to apoptosis and necrosis by Bcl-xL over-expression in rat hepatoma McA-RH8994 cells. J Gastroenterol Hepatol 14:682–690PubMedGoogle Scholar
  65. Gao G, Dou QP (2000) N-terminal cleavage of bax by calpain generates a potent proapoptotic 18-kDa fragment that promotes bcl-2-independent cytochrome c release and apoptotic cell death. J Cell Biochem 80:53–72PubMedGoogle Scholar
  66. Gharibyan AL, Zamotin V, Yanamandra K, Moskaleva OS, Margulis BA, Kostanyan IA, Morozova-Roche LA (2007) Lysozyme amyloid oligomers and fibrils induce cellular death via different apoptotic/necrotic pathways. J Mol Biol 365:1337–1349PubMedGoogle Scholar
  67. Goll DE, Thompson VF, Li H, Wei W, Cong J (2003) The calpain system. Physiol Rev 83:731–801PubMedGoogle Scholar
  68. Golstein P, Kroemer G (2007) Cell death by necrosis: Towards a molecular definition. Trends Biochem Sci 32:37–43PubMedGoogle Scholar
  69. Golstein P, Aubry L, Levraud JP (2003) Cell-death alternative model organisms: Why and which? Nat Rev Mol Cell Biol 4:798–807PubMedGoogle Scholar
  70. Gozuacik D, Kimchi A (2007) Autophagy and cell death. Curr Top Dev Biol 78:217–245PubMedGoogle Scholar
  71. Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312PubMedGoogle Scholar
  72. Haince JF, Rouleau M, Hendzel MJ, Masson JY, Poirier GG (2005) Targeting poly(ADP-ribosyl)ation: A promising approach in cancer therapy. Trends Mol Med 11:456–463PubMedGoogle Scholar
  73. Han W, Li L, Qiu S, Lu Q, Pan Q, Gu Y, Luo J, Hu X (2007) Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol Cancer Ther 6:1641–1649PubMedGoogle Scholar
  74. Hans G et al (2005) Beta-carbolines induce apoptosis in cultured cerebellar granule neurons via the mitochondrial pathway. Neuropharmacology 48:105–117PubMedGoogle Scholar
  75. Heeres JT, Hergenrother PJ (2007) Poly(ADP-ribose) makes a date with death. Curr Opin Chem Biol 11:644–653PubMedGoogle Scholar
  76. Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776PubMedGoogle Scholar
  77. Hirt UA, Gantner F, Leist M (2000) Phagocytosis of nonapoptotic cells dying by caspase-independent mechanisms. J Immunol 164:6520–6529PubMedGoogle Scholar
  78. Holcik M, Thompson CS, Yaraghi Z, Lefebvre CA, MacKenzie AE, Korneluk RG (2000) The hippocampal neurons of neuronal apoptosis inhibitory protein 1 (NAIP1)-deleted mice display increased vulnerability to kainic acid-induced injury. Proc Natl Acad Sci USA 97:2286–2290PubMedGoogle Scholar
  79. Holler N et al (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1:489–495PubMedGoogle Scholar
  80. Holt JA (1983) Cancer, a disease of defective glucose metabolism. Med Hypotheses 10:133–150PubMedGoogle Scholar
  81. Hong SJ, Dawson TM, Dawson VL (2004) Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol Sci 25:259–264PubMedGoogle Scholar
  82. Ikeda Y, Long DM (1990) The molecular basis of brain injury and brain edema: The role of oxygen free radicals. Neurosurgery 27:1–11PubMedGoogle Scholar
  83. Ishihara N et al (2005) Inhibition of apoptosis-inducing factor translocation is involved in protective effects of hepatocyte growth factor against excitotoxic cell death in cultured hippocampal neurons. J Neurochem 95:1277–1286PubMedGoogle Scholar
  84. Jaattela M (2002) Programmed cell death: Many ways for cells to die decently. Ann Med 34:480–488PubMedGoogle Scholar
  85. Jaattela M, Tschopp J (2003) Caspase-independent cell death in T lymphocytes. Nat Immunol 4:416–423PubMedGoogle Scholar
  86. Kehrer JP (1993) Free radicals as mediators of tissue injury and disease. Crit Rev Toxicol 23:21–48PubMedGoogle Scholar
  87. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257PubMedGoogle Scholar
  88. Kim GT, Chun YS, Park JW, Kim MS (2003a) Role of apoptosis-inducing factor in myocardial cell death by ischemia-reperfusion. Biochem Biophys Res Commun 309:619–624PubMedGoogle Scholar
  89. Kim JS, He L, Lemasters JJ (2003b) Mitochondrial permeability transition: A common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 304:463–470PubMedGoogle Scholar
  90. Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, Bronson RT, Ackerman SL (2002) The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature 419:367–374PubMedGoogle Scholar
  91. Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ (1995) Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270:96–99PubMedGoogle Scholar
  92. Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH (2000) Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 7:1166–1173PubMedGoogle Scholar
  93. Krantic S, Mechawar N, Reix S, Quirion R (2005) Molecular basis of programmed cell death involved in neurodegeneration. Trends Neurosci 28:670–676PubMedGoogle Scholar
  94. Krantic S, Mechawar N, Reix S, Quirion R (2007) Apoptosis-inducing factor: A matter of neuron life and death. Prog Neurobiol 81:179–196PubMedGoogle Scholar
  95. Kroemer G et al (2005) Classification of cell death: Recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ 12(Suppl 2):1463–1467PubMedGoogle Scholar
  96. Krysko DV, Denecker G, Festjens N, Gabriels S, Parthoens E, D’Herde K, Vandenabeele P (2006) Macrophages use different internalization mechanisms to clear apoptotic and necrotic cells. Cell Death Differ 13:2011–2022PubMedGoogle Scholar
  97. Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD (2002) Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111:331–342PubMedGoogle Scholar
  98. Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD (2005) BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17:525–535PubMedGoogle Scholar
  99. Leist M, Jaattela M (2001) Four deaths and a funeral: From caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2:589–598PubMedGoogle Scholar
  100. Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: A switch in the decision between apoptosis and necrosis. J Exp Med 185:1481–1486PubMedGoogle Scholar
  101. Leist M, Single B, Naumann H, Fava E, Simon B, Kuhnle S, Nicotera P (1999) Inhibition of mitochondrial ATP generation by nitric oxide switches apoptosis to necrosis. Exp Cell Res 249:396–403PubMedGoogle Scholar
  102. Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ (2002) Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2:183–192PubMedGoogle Scholar
  103. Li L, Han W, Gu Y, Qiu S, Lu Q, Jin J, Luo J, Hu X (2007) Honokiol induces a necrotic cell death through the mitochondrial permeability transition pore. Cancer Res 67:4894–4903PubMedGoogle Scholar
  104. Lindsten T et al (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6:1389–1399PubMedGoogle Scholar
  105. Lindsten T, Golden JA, Zong WX, Minarcik J, Harris MH, Thompson CB (2003) The proapoptotic activities of Bax and Bak limit the size of the neural stem cell pool. J Neurosci 23:11112–11119PubMedGoogle Scholar
  106. Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79:1431–1568PubMedGoogle Scholar
  107. Liu X, Schnellmann RG (2003) Calpain mediates progressive plasma membrane permeability and proteolysis of cytoskeleton-associated paxillin, talin, and vinculin during renal cell death. J Pharmacol Exp Ther 304:63–70PubMedGoogle Scholar
  108. Liu T, Brouha B, Grossman D (2004) Rapid induction of mitochondrial events and caspase-independent apoptosis in Survivin-targeted melanoma cells. Oncogene 23:39–48PubMedGoogle Scholar
  109. Loeffler M et al (2001) Dominant cell death induction by extramitochondrially targeted apoptosis-inducing factor. FASEB J 15:758–767PubMedGoogle Scholar
  110. Lorenzo HK, Susin SA (2004) Mitochondrial effectors in caspase-independent cell death. FEBS Lett 557:14–20PubMedGoogle Scholar
  111. Lorenzo HK, Susin SA (2007) Therapeutic potential of AIF-mediated caspase-independent programmed cell death. Drug Resist Update 10:235–255Google Scholar
  112. Mandic A, Viktorsson K, Strandberg L, Heiden T, Hansson J, Linder S, Shoshan MC (2002) Calpain-mediated Bid cleavage and calpain-independent Bak modulation: Two separate pathways in cisplatin-induced apoptosis. Mol Cell Biol 22:3003–3013PubMedGoogle Scholar
  113. Martinou I, Desagher S, Eskes R, Antonsson B, Andre E, Fakan S, Martinou JC (1999) The release of cytochrome c from mitochondria during apoptosis of NGF-deprived sympathetic neurons is a reversible event. J Cell Biol 144:883–889PubMedGoogle Scholar
  114. Mate MJ et al (2002) The crystal structure of the mouse apoptosis-inducing factor AIF. Nat Struct Biol 9:442–446PubMedGoogle Scholar
  115. Meli E, Pangallo M, Picca R, Baronti R, Moroni F, Pellegrini-Giampietro DE (2004) Differential role of poly(ADP-ribose) polymerase-1in apoptotic and necrotic neuronal death induced by mild or intense NMDA exposure in vitro. Mol Cell Neurosci 25:172–180PubMedGoogle Scholar
  116. Meli E, Baronti R, Pangallo M, Picca R, Moroni F, Pellegrini-Giampietro DE (2005) Group I metabotropic glutamate receptors stimulate the activity of poly(ADP-ribose) polymerase in mammalian mGlu1-transfected cells and in cortical cell cultures. Neuropharmacology 49(Suppl 1):80–88PubMedGoogle Scholar
  117. Meurette O, Rebillard A, Huc L, Le Moigne G, Merino D, Micheau O, Lagadic-Gossmann D, Dimanche-Boitrel MT (2007) TRAIL induces receptor-interacting protein 1-dependent and caspase-dependent necrosis-like cell death under acidic extracellular conditions. Cancer Res 67:218–226PubMedGoogle Scholar
  118. Miller TM, Moulder KL, Knudson CM, Creedon DJ, Deshmukh M, Korsmeyer SJ, Johnson EM Jr (1997) Bax deletion further orders the cell death pathway in cerebellar granule cells and suggests a caspase-independent pathway to cell death. J Cell Biol 139:205–217PubMedGoogle Scholar
  119. Miramar MD et al (2001) NADH oxidase activity of mitochondrial apoptosis-inducing factor. J Biol Chem 276:16391–16398PubMedGoogle Scholar
  120. Moroni F (2008) Poly(ADP-ribose)polymerase 1 (PARP-1) and postischemic brain damage. Curr Opin Pharmacol 8:96–103PubMedGoogle Scholar
  121. Moroni F et al (2001) Poly(ADP-ribose) polymerase inhibitors attenuate necrotic but not apoptotic neuronal death in experimental models of cerebral ischemia. Cell Death Differ 8:921–932PubMedGoogle Scholar
  122. Moubarak RS, Yuste VJ, Artus C, Bouharrour A, Greer PA, Menissier-de Murcia J, Susin SA (2007) Sequential activation of poly(ADP-ribose) polymerase 1, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis. Mol Cell Biol 27:4844–4862PubMedGoogle Scholar
  123. Munoz-Pinedo C, Guio-Carrion A, Goldstein JC, Fitzgerald P, Newmeyer DD, Green DR (2006) Different mitochondrial intermembrane space proteins are released during apoptosis in a manner that is coordinately initiated but can vary in duration. Proc Natl Acad Sci USA 103:11573–11578PubMedGoogle Scholar
  124. Murahashi H et al (2003) Possible contribution of apoptosis-inducing factor (AIF) and reactive oxygen species (ROS) to UVB-induced caspase-independent cell death in the T cell line Jurkat. J Leukoc Biol 73:399–406PubMedGoogle Scholar
  125. Nakagawa T et al (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434:652–658PubMedGoogle Scholar
  126. Nath R et al (1996) Non-erythroid alpha-spectrin breakdown by calpain and interleukin 1 beta-converting-enzyme-like protease(s) in apoptotic cells: contributory roles of both protease families in neuronal apoptosis. Biochem J 319(Pt 3):683–690PubMedGoogle Scholar
  127. Nelson WG (2004) Prostate cancer prevention. J Nutr 134:3211S–3212SPubMedGoogle Scholar
  128. Nicotera P, Leist M, Manzo L (1999a) Neuronal cell death: A demise with different shapes. Trends Pharmacol Sci 20:46–51PubMedGoogle Scholar
  129. Nicotera P, Leist M, Ferrando-May E (1999b) Apoptosis and necrosis: Different execution of the same death. Biochem Soc Symp 66:69–73PubMedGoogle Scholar
  130. Niimura M et al (2006) Prevention of apoptosis-inducing factor translocation is a possible mechanism for protective effects of hepatocyte growth factor against neuronal cell death in the hippocampus after transient forebrain ischemia. J Cereb Blood Flow Metab 26:1354–1365PubMedGoogle Scholar
  131. Niquet J, Seo DW, Wasterlain CG (2006) Mitochondrial pathways of neuronal necrosis. Biochem Soc Trans 34:1347–1351PubMedGoogle Scholar
  132. Nishimura Y, Lemasters JJ (2001) Glycine blocks opening of a death channel in cultured hepatic sinusoidal endothelial cells during chemical hypoxia. Cell Death Differ 8:850–858PubMedGoogle Scholar
  133. Nixon RA (2006) Autophagy in neurodegenerative disease: Friend, foe or turncoat? Trends Neurosci 29:528–535PubMedGoogle Scholar
  134. Ohgoh M, Shimizu H, Ogura H, Nishizawa Y (2000) Astroglial trophic support and neuronal cell death: Influence of cellular energy level on type of cell death induced by mitochondrial toxin in cultured rat cortical neurons. J Neurochem 75:925–933PubMedGoogle Scholar
  135. Okada H, Mak TW (2004) Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 4:592–603PubMedGoogle Scholar
  136. Oo TF, Blazeski R, Harrison SM, Henchcliffe C, Mason CA, Roffler-Tarlov SK, Burke RE (1996) Neuron death in the substantia nigra of weaver mouse occurs late in development and is not apoptotic. J Neurosci 16:6134–6145PubMedGoogle Scholar
  137. Oppenheim RW, Flavell RA, Vinsant S, Prevette D, Kuan CY, Rakic P (2001) Programmed cell death of developing mammalian neurons after genetic deletion of caspases. J Neurosci 21:4752–4760PubMedGoogle Scholar
  138. Orrenius S, Zhivotovsky B (2006) The future of toxicology – does it matter how cells die? Chem Res Toxicol 19:729–733PubMedGoogle Scholar
  139. Otera H, Ohsakaya S, Nagaura Z, Ishihara N, Mihara K (2005) Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space. EMBO J 24:1375–1386PubMedGoogle Scholar
  140. Pastorino JG, Chen ST, Tafani M, Snyder JW, Farber JL (1998) The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J Biol Chem 273:7770–7775PubMedGoogle Scholar
  141. Perrelet D et al (2000) IAP family proteins delay motoneuron cell death in vivo. Eur J Neurosci 12:2059–2067PubMedGoogle Scholar
  142. Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K (2004) Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab 24:458–466PubMedGoogle Scholar
  143. Polster BM, Basanez G, Etxebarria A, Hardwick JM, Nicholls DG (2005) Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. J Biol Chem 280:6447–6454PubMedGoogle Scholar
  144. Rao RV, Castro-Obregon S, Frankowski H, Schuler M, Stoka V, del Rio G, Bredesen DE, Ellerby HM (2002) Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. J Biol Chem 277:21836–21842PubMedGoogle Scholar
  145. Saelens X, Festjens N, Parthoens E, Vanoverberghe I, Kalai M, van Kuppeveld F, Vandenabeele P (2005) Protein synthesis persists during necrotic cell death. J Cell Biol 168:545–551PubMedGoogle Scholar
  146. Saez ME, Ramirez-Lorca R, Moron FJ, Ruiz A (2006) The therapeutic potential of the calpain family: New aspects. Drug Discov Today 11:917–923PubMedGoogle Scholar
  147. Saito A et al (2005) Oxidative stress and neuronal death/survival signaling in cerebral ischemia. Mol Neurobiol 31:105–116PubMedGoogle Scholar
  148. Sattler R, Tymianski M (2001) Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Mol Neurobiol 24:107–129PubMedGoogle Scholar
  149. Schinzel AC et al (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci USA 102:12005–12010PubMedGoogle Scholar
  150. Schreiber V, Dantzer F, Ame JC, de Murcia G (2006) Poly(ADP-ribose): Novel functions for an old molecule. Nat Rev Mol Cell Biol 7:517–528PubMedGoogle Scholar
  151. Schweichel JU, Merker HJ (1973) The morphology of various types of cell death in prenatal tissues. Teratology 7:253–266Google Scholar
  152. Scorrano L, Korsmeyer SJ (2003) Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun 304:437–444PubMedGoogle Scholar
  153. Seye CI, Knaapen MW, Daret D, Desgranges C, Herman AG, Kockx MM, Bult H (2004) 7-Ketocholesterol induces reversible cytochrome c release in smooth muscle cells in absence of mitochondrial swelling. Cardiovasc Res 64:144–153PubMedGoogle Scholar
  154. Shall S, de Murcia G (2000) Poly(ADP-ribose) polymerase-1: What have we learned from the deficient mouse model? Mutat Res 460:1–15PubMedGoogle Scholar
  155. Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, Tsujimoto Y (2004) Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 6:1221–1228PubMedGoogle Scholar
  156. Skaper SD (2003) Poly(ADP-Ribose) polymerase-1 in acute neuronal death and inflammation: A strategy for neuroprotection. Ann N Y Acad Sci 993:217–228; discussion 287–288Google Scholar
  157. Sorimachi H, Suzuki K (2001) The structure of calpain. J Biochem (Tokyo) 129:653–664Google Scholar
  158. Sperandio S, de Belle I, Bredesen DE (2000) An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci USA 97:14376–14381PubMedGoogle Scholar
  159. Srivastava S et al (2007) Apoptosis-inducing factor regulates death in peripheral T cells. J Immunol 179:797–803PubMedGoogle Scholar
  160. Stadelmann C, Bruck W, Bancher C, Jellinger K, Lassmann H (1998) Alzheimer disease: DNA fragmentation indicates increased neuronal vulnerability, but not apoptosis. J Neuropathol Exp Neurol 57:456–464PubMedGoogle Scholar
  161. Stadtman ER, Oliver CN (1991) Metal-catalyzed oxidation of proteins. Physiological consequences. J Biol Chem 266:2005–2008PubMedGoogle Scholar
  162. Stoica BA, Movsesyan VA, Knoblach SM, Faden AI (2005) Ceramide induces neuronal apoptosis through mitogen-activated protein kinases and causes release of multiple mitochondrial proteins. Mol Cell Neurosci 29:355–371PubMedGoogle Scholar
  163. Strasser A et al (2000) The role of bim, a proapoptotic BH3-only member of the Bcl-2 family in cell-death control. Ann N Y Acad Sci 917:541–548PubMedGoogle Scholar
  164. Strosznajder R, Gajkowska B (2006) Effect of 3-aminobenzamide on Bcl-2, Bax and AIF localization in hippocampal neurons altered by ischemia-reperfusion injury. The immunocytochemical study. Acta Neurobiol Exp (Wars) 66:15–22Google Scholar
  165. Susin SA et al (1996) Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J Exp Med 184:1331–1341PubMedGoogle Scholar
  166. Susin SA et al (1997) The central executioner of apoptosis: Multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis. J Exp Med 186:25–37PubMedGoogle Scholar
  167. Susin SA et al (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446PubMedGoogle Scholar
  168. Susin SA et al (2000) Two distinct pathways leading to nuclear apoptosis. J Exp Med 192:571–580PubMedGoogle Scholar
  169. Tan Y, Dourdin N, Wu C, De Veyra T, Elce JS, Greer PA (2006) Conditional disruption of ubiquitous calpains in the mouse. Genesis 44:297–303PubMedGoogle Scholar
  170. Thornberry NA, Lazebnik Y (1998) Caspases: Enemies within. Science 281:1312–1316PubMedGoogle Scholar
  171. Toyota H, Yanase N, Yoshimoto T, Moriyama M, Sudo T, Mizuguchi J (2003) Calpain-induced Bax-cleavage product is a more potent inducer of apoptotic cell death than wild-type Bax. Cancer Lett 189:221–230PubMedGoogle Scholar
  172. Tsujimoto Y (2002) Bcl-2 family of proteins: life-or-death switch in mitochondria. Biosci Rep 22:47–58PubMedGoogle Scholar
  173. Unal-Cevik I, Kilinc M, Can A, Gursoy-Ozdemir Y, Dalkara T (2004) Apoptotic and necrotic death mechanisms are concomitantly activated in the same cell after cerebral ischemia. Stroke 35:2189–2194PubMedGoogle Scholar
  174. Vahsen N et al (2004) AIF deficiency compromises oxidative phosphorylation. EMBO J 23:4679–4689PubMedGoogle Scholar
  175. van Wijk SJ, Hageman GJ (2005) Poly(ADP-ribose) polymerase-1 mediated caspase-independent cell death after ischemia/reperfusion. Free Radic Biol Med 39:81–90PubMedGoogle Scholar
  176. Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S, Hakem R, Greenberg AH (2000) BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol 20:5454–5468PubMedGoogle Scholar
  177. Vanden Berghe T, van Loo G, Saelens X, Van Gurp M, Brouckaert G, Kalai M, Declercq W, Vandenabeele P (2004) Differential signaling to apoptotic and necrotic cell death by Fas-associated death domain protein FADD. J Biol Chem 279:7925–7933PubMedGoogle Scholar
  178. Wang X, Yang C, Chai J, Shi Y, Xue D (2002) Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans. Science 298:1587–1592PubMedGoogle Scholar
  179. Wang HM, Shimoji M, Yu SW, Dawson TM, Dawson VL (2003) Apoptosis inducing factor and PARP-mediated injury in the MPTP mouse model of Parkinson’s disease. In: Federoff H (eds) Parkinson’s disease: The life cycle of the dopamine neuron. New York Acad Sciences, New York, pp 132–139Google Scholar
  180. Wang H et al (2004) Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death. J Neurosci 24:10963–10973PubMedGoogle Scholar
  181. Wang Y, Han R, Liang ZQ, Wu JC, Zhang XD, Gu ZL, Qin ZH (2008) An autophagic mechanism is involved in apoptotic death of rat striatal neurons induced by the non-N-methyl-d-aspartate receptor agonist kainic acid. Autophagy 4:214–226PubMedGoogle Scholar
  182. Waring P (2005) Redox active calcium ion channels and cell death. Arch Biochem Biophys 434:33–42PubMedGoogle Scholar
  183. Wei MC et al (2001) Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science 292:727–730PubMedGoogle Scholar
  184. Whiteman M et al (2007) The pro-inflammatory oxidant hypochlorous acid induces Bax-dependent mitochondrial permeabilisation and cell death through AIF-/EndoG-dependent pathways. Cell Signal 19:705–714PubMedGoogle Scholar
  185. Willis SN, Adams JM (2005) Life in the balance: How BH3-only proteins induce apoptosis. Curr Opin Cell Biol 17:617–625PubMedGoogle Scholar
  186. Willis SN et al (2007) Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315:856–859PubMedGoogle Scholar
  187. Wood DE, Thomas A, Devi LA, Berman Y, Beavis RC, Reed JC, Newcomb EW (1998) Bax cleavage is mediated by calpain during drug-induced apoptosis. Oncogene 17:1069–1078PubMedGoogle Scholar
  188. Wright KM, Linhoff MW, Potts PR, Deshmukh M (2004) Decreased apoptosome activity with neuronal differentiation sets the threshold for strict IAP regulation of apoptosis. J Cell Biol 167:303–313PubMedGoogle Scholar
  189. Xiong ZG et al (2004) Neuroprotection in ischemia: Blocking calcium-permeable acid-sensing ion channels. Cell 118:687–698PubMedGoogle Scholar
  190. Ye H et al (2002) DNA binding is required for the apoptogenic action of apoptosis inducing factor. Nat Struct Biol 9:680–684PubMedGoogle Scholar
  191. Youle RJ, Strasser A (2008) The BCL-2 protein family: Opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59PubMedGoogle Scholar
  192. Yu SW et al (2002) Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297:259–263PubMedGoogle Scholar
  193. Yu SW, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, Dawson VL (2006) Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc Natl Acad Sci USA 103:18314–18319PubMedGoogle Scholar
  194. Yuste VJ et al (2005a) The contribution of apoptosis-inducing factor, caspase-activated DNase, and inhibitor of caspase-activated DNase to the nuclear phenotype and DNA. J Biol Chem 280:35670–35683PubMedGoogle Scholar
  195. Yuste VJ, Moubarak RS, Delettre C, Bras M, Sancho P, Robert N, d’Alayer J, Susin SA (2005b) Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release. Cell Death Differ 12:1445–1448PubMedGoogle Scholar
  196. Zhang X et al (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 82:181–191PubMedGoogle Scholar
  197. Zhu C, Qiu L, Wang X, Hallin U, Cande C, Kroemer G, Hagberg H, Blomgren K (2003) Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain. J Neurochem 86:306–317PubMedGoogle Scholar
  198. Zhu C, Wang X, Qiu L, Peeters-Scholte C, Hagberg H, Blomgren K (2004) Nitrosylation precedes caspase-3 activation and translocation of apoptosis-inducing factor in neonatal rat cerebral hypoxia-ischaemia. J Neurochem 90:462–471PubMedGoogle Scholar
  199. Zhu C, Xu F, Wang X, Shibata M, Uchiyama Y, Blomgren K, Hagberg H (2006) Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia-ischaemia. J Neurochem 96:1016–1027PubMedGoogle Scholar
  200. Zhu C et al (2007) Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia. Cell Death Differ 14:775–784PubMedGoogle Scholar
  201. Zolotarjova N, Ho C, Mellgren RL, Askari A, Huang WH (1994) Different sensitivities of native and oxidized forms of Na+/K(+)-ATPase to intracellular proteinases. Biochim Biophys Acta 1192:125–131PubMedGoogle Scholar
  202. Zong WX, Thompson CB (2006) Necrotic death as a cell fate. Genes Dev 20:1–15PubMedGoogle Scholar
  203. Zong WX, Ditsworth D, Bauer DE, Wang ZQ, Thompson CB (2004) Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev 18:1272–1282PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Institut de Neurobiologie de la Méditerranée (INMED)/U29 INSERMParc Scientifique de LuminyMarseilleFrance
  2. 2.INSERM, U872, Team 19, Centre de Recherche des CordeliersParisFrance
  3. 3.France Université Pierre et Marie Curie-Paris 6, UMRS 872ParisFrance
  4. 4.France Université Paris Descartes, UMRS 872ParisFrance

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