----------------------------------------------------------------------- BIOINFORMATICS COLLOQUIUM College of Science George Mason University ----------------------------------------------------------------------- New links between mitochondrial morphogenesis and apoptosis Richard J. Youle, Ph.D. NINDS NIH Abstract: Bcl-2 family members are important regulators of apoptosis and localize to mitochondria. We find that during apoptosis, two pro-apoptotic members of the Bcl-2 family,Bax and Bak, coalesce into foci on the mitochondrial membrane at sites where mitochondria subsequently divide, that mitochondria divide into multiple smaller units and that cytochrome c is released, all at about the same time. The mitochondrial fragmentation process occurs independently and upstream of the caspase activation step of apoptosis. In vitro in cultured mammalian cells as well as in vivo during D. melanogaster and C. elegans development, inhibition of the normal mitochondrial division machinery not only inhibits the mitochondrial fragmentation process that occurs during apoptosis but also inhibits or delays the cell death process itself. This suggests that the mitochondrial division machinery normally plays an important role in programmed cell death induction. In healthy cells Bax and Bak are required for normal mitochondrial fusion activity linking Bcl-2 family member proteins to mitochondrial morphogenesis even beyond cell death processes. One component of the mitochondrial morphogenesis machinery appears to be linked directly to Bax. An endophilin isoform identified in yeast two hybrid as a Bax binding protein, is specifically involved in coupling division of the outer mitochondrial membrane to that of the inner membrane in healthy cells. Recent results show how Endophilins may couple membrane biogenesis processes to Bcl-2 family regulation of programmed cell death.