Molecular characterization of mitochondrial apoptosis-inducing factor

Santos A. Susin, Hans K. Lorenzo, Naoufal Zamzami, Isabel Marzo, Bryan E. Snow, Greg M. Brothers, Joan Mangion, Etienne Jacotot, Paola Costantini, Markus Loeffler, Nathanael Larochette, David R. Goodlett, Ruedi Aebersold, David P. Siderovski, Josef M. Penninger and Guido Kroemer ()
Additional contact information
Santos A. Susin: Centre National de la Recherche Scientifique, UPR 420
Hans K. Lorenzo: Unit de Biochimie Structurale, Institut Pasteur
Naoufal Zamzami: Centre National de la Recherche Scientifique, UPR 420
Isabel Marzo: Centre National de la Recherche Scientifique, UPR 420
Bryan E. Snow: The Amgen Institute and Ontario Cancer Institute, University of Toronto
Greg M. Brothers: The Amgen Institute and Ontario Cancer Institute, University of Toronto
Joan Mangion: The Amgen Institute and Ontario Cancer Institute, University of Toronto
Etienne Jacotot: Centre National de la Recherche Scientifique, UPR 420
Paola Costantini: Centre National de la Recherche Scientifique, UPR 420
Markus Loeffler: Centre National de la Recherche Scientifique, UPR 420
Nathanael Larochette: Centre National de la Recherche Scientifique, UPR 420
David R. Goodlett: University of Washington
Ruedi Aebersold: University of Washington
David P. Siderovski: The Amgen Institute and Ontario Cancer Institute, University of Toronto
Josef M. Penninger: The Amgen Institute and Ontario Cancer Institute, University of Toronto
Guido Kroemer: Centre National de la Recherche Scientifique, UPR 420

Nature, 1999, vol. 397, issue 6718, 441-446

Abstract: Abstract Mitochondria play a key part in the regulation of apoptosis (cell death)1,2. Their intermembrane space contains several proteins that are liberated through the outer membrane in order to participate in the degradation phase of apoptosis3,4,5,6,7,8,9. Here we report the identification and cloning of an apoptosis-inducing factor, AIF5, which is sufficient to induce apoptosis of isolated nuclei. AIF is a flavoprotein of relative molecular mass 57,000 which shares homology with the bacterial oxidoreductases; it is normally confined to mitochondria but translocates to the nucleus when apoptosis is induced. Recombinant AIF causes chromatin condensation in isolated nuclei and large-scale fragmentation of DNA. It induces purified mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Microinjection of AIF into the cytoplasm of intact cells induces condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of these effects is prevented by the wide-ranging caspase inhibitor known as Z-VAD.fmk. Overexpression of Bcl-2, which controls the opening of mitochondrial permeability transition pores, prevents the release of AIF from the mitochondrion but does not affect its apoptogenic activity. These results indicate that AIF is a mitochondrial effector of apoptotic cell death.

Date: 1999
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DOI: 10.1038/17135

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