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

Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in... 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 . mitochondria; AIF; caspases; Bax; Bid Footnotes ↵ * Abbreviations used in this paper: AIF, apoptosis-inducing factor; Cox IV, cytochrome c oxidase subunit IV; H 2 O 2 , hydrogen peroxide; MIM, mitochondrial inner membrane; MOM, mitochondrial outer membrane; MP, mitoplast. The online version of this article contains supplemental material. Submitted: 15 July 2002 Accepted: 8 November 2002 Revision received 4 November 2002 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Cell Biology Rockefeller University Press

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

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Publisher
Rockefeller University Press
Copyright
Copyright © 2002, by The Rockefeller University Press
ISSN
0021-9525
eISSN
1540-8140
DOI
10.1083/jcb.200207071
Publisher site
See Article on Publisher Site

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 . mitochondria; AIF; caspases; Bax; Bid Footnotes ↵ * Abbreviations used in this paper: AIF, apoptosis-inducing factor; Cox IV, cytochrome c oxidase subunit IV; H 2 O 2 , hydrogen peroxide; MIM, mitochondrial inner membrane; MOM, mitochondrial outer membrane; MP, mitoplast. The online version of this article contains supplemental material. Submitted: 15 July 2002 Accepted: 8 November 2002 Revision received 4 November 2002

Journal

The Journal of Cell BiologyRockefeller University Press

Published: Dec 23, 2002

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