The Bcl-2 family of proteins regulate apoptosis by controlling mitochondrial permeability and the release of cytochrome C. The anti-apoptotic proteins Bcl-2 and Bcl-xL reside in the outer mitochondrial wall and inhibit cytochrome C release. The pro-apoptotic Bcl-2 proteins Bad, Bid, Bax and Bim reside in the cytosol but translocate to mitochondria following death signaling, where they promote the release of cytochrome C. Bad translocates to mitochondria and forms a pro-apoptotic complex with Bcl-xL. This translocation is inhibited by survival factors that induce the phosphorylation of Bad, leading to its cytosolic sequestration. Cytosolic BID is cleaved by caspase 8 following signaling through Fas: its active fragment (tBid) translocates to mitochondria. Bax and Bim translocate to mitochondria in response to death stimuli, including survival factor withdrawal. p53, activated following DNA damage, induces the transcription of Bax. Released cytochrome C binds Apaf1 and forms an activation complex with caspase 9. Although the mechanism(s) regulating mitochondrial permeability and the release of cytochrome C during apoptosis are not fully understood, Bcl-xL, Bcl-2 and Bax apparently influence the voltage-dependent anion channel (VDAC), which can control cytochrome C release.
