APOPTOSIS Caspases Required for AIF Release

Apoptosis-inducing factor (AIF) is a mitochondrial protein that is released during programmed cell death and contributes to DNA fragmentation. AIF-induced cell death has been described as a caspase-independent death pathway. Arnoult et al. examined release of cytochrome c and AIF from mitochondria in response to various apoptosis-initiating stimuli: exposure to the proapoptotic Bax protein, exposure to Bax and tBid, staurosporine, or actinomycin D. Exposure of purified mitochondria to Bax did not cause release of AIF, but did cause release of cytochrome c. AIF was found to be a peripheral membrane protein associated with the inner mitochondrial membrane that was not soluble in the intermembrane space. Exposure of cultured or primary cells to Bax or the apoptosis-inducing drugs caused release of both cytochrome c and AIF and cell death. However, release of AIF was specifically blocked if caspase inhibitors were added, which also prevented cell death. The authors suggest that Bax association with the mitochondria promotes the release of cytochrome c, which is soluble in the intermembrane space, but that release of AIF requires caspase activation to ultimately allow AIF to be released from the inner mitochondrial membrane into the cytosol. Thus, the caspase-independent pathway may not be so independent after all.

D. Arnoult, P. Parone, J.-C. Martinou, B. Antonsson, J. Estaquier, J. C. Ameisen, Mitochondrial relase of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli. J. Cell Biol. 159, 923-929 (2002). [Abstract] [Full Text]

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

Damien Arnoult, Philippe Parone, Jean-Claude Martinou, Bruno Antonsson, Jérôme Estaquier, and Jean Claude Ameisen (23 December 2002)
J. Cell Biol. 159 (6), 923. [DOI: 10.1083/jcb.200207071]
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