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Mitochondrial Implication in Accidental and Programmed Cell Death: Apoptosis and Necrosis

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Abstract

Both physiological cell death (apoptosis) and at least some cases of accidental cell death (necrosis) involve a two-step-process. At a first level, numerous physiological or pathological stimuli can trigger mitochondrial permeability transition which constitutes a rate-limiting event and initiates the common phase of the death process. Mitochondrial permeability transition (FT) involves the formation of proteaceous, regulated pores, probably by apposition of inner and outer mitochondrial membrane proteins which cooperate to form the mitochondrial PT pore complex. Inhibition of PT by pharmacological intervention on mitochondrial structures or mitochondrial expression of the apoptosis-inhibitory oncoprotein Bcl-2 thus can prevent cell death. At a second level, the consequences of mitochondrial dysfunction (collapse of the mitochondrial transmembrane potential, uncoupling of the respiratory chain, hyperproduction of superoxide anions, disruption of mitochondrial biogenesis, outflow of matrix calcium and glutathione, and release of soluble intermembrane proteins) can entail a bioenergetic catastrophe culminating in the disruption of plasma membrane integrity (necrosis) and/or the activation and action of apoptogenic proteases with secondary endonuclease activation and consequent oligonucleosomal DNA fragmentation (apoptosis). The acquisition of the biochemical and ultrastructural features of apoptosis critically relies on the liberation of apoptogenic proteases or protease activators from the mitochondrial intermembrane space. This scenario applies to very different models of cell death. The notion that mitochondrial events control cell death has major implications for the development of death-inhibitory drugs.

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  1. Centre National de la Recherche Scientifique-UPR420, 19 rue Guy Môquet, B.P. 8, F-94801, Villejuif, France

    Naoufal Zamzami, Tamara Hirsch, Bruno Dallaporta, Patrice X. Petit & Guido Kroemer

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  1. Naoufal Zamzami
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Zamzami, N., Hirsch, T., Dallaporta, B. et al. Mitochondrial Implication in Accidental and Programmed Cell Death: Apoptosis and Necrosis. J Bioenerg Biomembr 29, 185–193 (1997). https://doi.org/10.1023/A:1022694131572

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