Module 11: Figure Bcl-2 family functions
Intrinsic apoptotic events at the mitochondrion responsible for the release of cytochrome c and the formation of the apoptosome.
A critical event of the intrinsic pathway is the release of cytochrome c (Cyt c) through mechanisms that are still being investigated. One hypothesis considers that formation of the mitochondrial permeability transition pore (mPTP) provides an avenue for cytochrome c to pass across the outer mitochondrial membrane (OMM). Another hypothesis is that Cyt c passes across channels formed by the polymerization of pro-apoptotic factors such as Bak and Bax, which are members of the Bcl-2 superfamily. Whether or not Bax and Bak can polymerize depends on a complex web of interactions with other members of the Bcl-2 superfamily. Bax is kept quiescent by being bound to the anti-apoptotic factor Bcl-2, but the inhibitory action can be negated by the pro-apoptotic factor Bim. Likewise, Bak is inhibited by Bcl-XL, but this inhibition can be reversed by Bad. The ability of Bad to remove Bcl-XL is regulated by the PtdIns 3-kinase signalling pathway, which acts through protein kinase B (PKB) that phosphorylates Bad, which is then taken out of action by being bound to 14-3-3 protein.