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J. Cell Biol. 159 (6): 923-929

Copyright © 2002 by the Rockefeller University Press.

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Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli

Damien Arnoult1, Philippe Parone2, Jean-Claude Martinou2, Bruno Antonsson3, Jérôme Estaquier1, and Jean Claude Ameisen1

1 EMI-U 9922 Institut National de la Santé et de la Recherche Medicale (INSERM)/Université Paris 7, IFR02, AP-HP, CHU Bichat, 75018 Paris, France
2 Department of Cell Biology, University of Geneva, 1211 Geneva 4, Switzerland
3 Serono Pharmaceutical Research Institute, Serono International SA, CH-1228 Plan-les-Ouates, Geneva, Switzerland

Address correspondence to D. Arnoult, National Institutes of Health/National Institute of Neurological Disorders and Stroke, Biochemistry section, Bldg. 10, Rm. 4N258, Bethesda, MD 20892. Tel.: (301) 496-6628. Fax: (301) 402-0380. E-mail: ArnoultD{at}ninds.nih.gov; or J.C. Ameisen, EMI-U 9922 INSERM, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, BP 416, 75870 Paris cedex 18, France. Tel.: 33-1-44-85-61-50. Fax: 33-1-44-85-61-49. E-mail: ants{at}club-internet.fr

Abstract: Mitochondrial outer membrane permeabilization by proapoptotic Bcl-2 family proteins, such as Bax, plays a crucial role in apoptosis induction. However, whether this only causes the intracytosolic release of inducers of caspase-dependent death, such as cytochrome c, or also of caspase-independent death, such as apoptosis-inducing factor (AIF) remains unknown. Here, we show that on isolated mitochondria, Bax causes the release of cytochrome c, but not of AIF, and the association of AIF with the mitochondrial inner membrane provides a simple explanation for its lack of release upon Bax-mediated outer membrane permeabilization. In cells overexpressing Bax or treated either with the Bax- or Bak-dependent proapoptotic drugs staurosporine or actinomycin D, or with hydrogen peroxide, caspase inhibitors did not affect the intracytosolic translocation of cytochrome c, but prevented that of AIF. These results provide a paradigm for mitochondria-dependent death pathways in which AIF cannot substitute for caspase executioners because its intracytosolic release occurs downstream of that of cytochrome c.

Key Words: mitochondria; AIF; caspases; Bax; Bid

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