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TY - JOUR AU - Susin, Santos A. AU - Lorenzo, Hans K. AU - Zamzami, Naoufal AU - Marzo, Isabel AU - Snow, Bryan E. AU - Brothers, Greg M. AU - Mangion, Joan AU - Jacotot, Etienne AU - Costantini, Paola AU - Loeffler, Markus AU - Larochette, Nathanael AU - Goodlett, David R. AU - Aebersold, Ruedi AU - Siderovski, David P. AU - Penninger, Josef M. AU - Kroemer, Guido PY - 1999 DA - 1999/02/01 TI - Molecular characterization of mitochondrial apoptosis-inducing factor JO - Nature SP - 441 EP - 446 VL - 397 IS - 6718 AB - 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. SN - 1476-4687 UR - https://doi.org/10.1038/17135 DO - 10.1038/17135 ID - Susin1999 ER -