Mitochondrial dysfunction in cell death.

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DESCRIPTION (provided by applicant): Mitochondria play a central role in apoptosis (programmed cell death). In particular, the release of proteins, such as cytochrome c and Smac/DIABLO from the mitochondrial intermembrane space into the cytosol is an important trigger for caspase activation, which in turn leads to the events characteristic of apoptosis. Here we propose studies exploring aspects of this apoptotic pathway involving mitochondria. First, we address the interaction of cytochrome c with the Apaf- 1 protein, a step required for caspase-9 activation. Second, we investigate the changes in mitochondrial function resulting from outer membrane permeabilization; under circumstances where caspases are inhibited, these mitochondrial effects may be responsible for the death of the cell. Finally, we explore the nature of the outer mitochondrial membrane permeabilization event, particularly with regard to its regulation by pro- and anti-apoptotic Bcl-2 family proteins such as Bid, Bax and Bcl-xL.