Mitochondria as regulators of apoptosis: Doubt no more

Santos A. Susin, Naoufal Zamzami, Guido Kroemer

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768 Citations (Scopus)

Abstract

Scientific revolution [1] implies a transformation of the world view in which a dominant paradigm is substituted by a new one, one which furnishes an ameliorated comprehension of facts, as well as an advantage for the design of informative experiments. Apoptosis research has recently experienced a change from a paradigm in which the nucleus determined the apoptotic process to a paradigm in which mitochondria constitute the center of death control. Several pieces of evidence imply mitochondria in the process of apoptosis. Kinetic data indicate that mitochondria undergo major changes in membrane integrity before classical signs of apoptosis become manifest. These changes concern both the inner and the outer mitochondrial membranes, leading to a disruption of the inner transmembrane potential (ΔΨ(m)) and the release of intermembrane proteins through the outer membrane. Cell-free systems of apoptosis demonstrate that mitochondrial products are rate limiting for the activation of caspases and endonucleases in cell extracts. Functional studies indicate that drug-enforced opening or closing of the mitochondrial megachannel (also called permeability transition pore) can induce or prevent apoptosis. The anti-apoptotic oncoprotein Bcl-2 acts on mitochondria to stabilize membrane integrity and to prevent opening of the megachannel. These observations are compatible with a three-step model of apoptosis: a premitochondrial phase during which signal transduction cascades or damage pathways are activated; a mitochondrial phase, during which mitochondrial membrane function is lost; and a post-mitochondrial phase, during which proteins released from mitochondria cause the activation of catabolic proteases and nucleases. The implication of mitochondria in apoptosis has important consequences for the understanding of the normal physiology of apoptosis, its deregulation in cancer and degenerative diseases, and the development of novel cytotoxic and cytoprotective drugs. Copyright (C) 1998 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)151-165
Number of pages15
JournalBiochimica et Biophysica Acta - Bioenergetics
Volume1366
Issue number1-2
DOIs
Publication statusPublished - 10 Aug 1998
Externally publishedYes

Keywords

  • Apoptosis
  • Bcl-2
  • Necrosis
  • Permeability transition
  • Programmed death

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