Proapoptotic BH3-only Bcl-2 family members induce cytochromecrelease, but not mitochondrial membrane potential loss, and do not directly modulate voltage-dependent anion channel activity

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Abstract
Through direct interaction with the voltage-dependent anion channel (VDAC), proapoptotic Bcl-2 family members such as Bax and Bak induce apoptogenic mitochondrial cytochromecrelease and membrane potential (Δψ) loss in isolated mitochondria. Using isolated mitochondria, we showed that Bid and Bik, BH3-only proteins from the Bcl-2 family, induced cytochromecrelease but not Δψ loss. Unlike Bax/Bak, the cytochromecrelease induced by Bid/Bik was Ca2+-independent, cyclosporin A-insensitive, and respiration-independent. Furthermore, in contrast to Bax/Bak, Bid/Bik neither interacted with VDAC nor directly affected the VDAC activity in liposomes. Consistently, Bid/Bik induced apoptosis without Δψ loss, whereas Bax induced apoptosis with Δψ loss. These findings indicated the involvement of a different mechanism in BH3-only, protein-induced apoptogenic cytochromecrelease.

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