Molecular characterization of mitochodrial 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, Guido Kroemer

Research output: Contribution to journalArticlepeer-review

3261 Scopus citations

Abstract

Mitochondria play a key part in the regulation of apoptosis (cell death). Their intermembrane space contains several proteins that are liberated through the outer membrane in order to participate in the degradation phase of apoptosis. Here we report the identification and cloning of an apoptosis-inducing factor, AIF, 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 oxiforeductases; 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.

Original languageEnglish
Pages (from-to)441-446
Number of pages6
JournalNature
Volume397
Issue number6718
DOIs
StatePublished - 4 Feb 1999

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