Abstract

Truncated BID (tBID), a proapoptotic BCL2 family protein, induces BAK/BAX-dependent release of cytochrome c and other mitochondrial intermembrane proteins to the cytosol to induce apoptosis. The voltage-dependent anion channels (VDACs) are the primary gates for solutes across the outer mitochondrial membrane (OMM); however, their role in apoptotic OMM permeabilization remains controversial. Here, we report that VDAC2^-/- (V2^-/-) mouse embryonic fibroblasts (MEFs) are virtually insensitive to tBID-induced OMM permeabilization and apoptosis, whereas VDAC1^-/-, VDAC3^-/- and VDAC1^-/-/VDAC3^-/- MEFs respond normally to tBID. V2^-/- MEFs regain tBID sensitivity after VDAC2 expression. Furthermore, V2^-/- MEFs are deficient in mitochondrial BAK despite normal tBID–mitochondrial binding and BAX/BAK expression. tBID sensitivity of BAK^-/- MEFs is also reduced, although not to the same extent as V2^-/- MEFs, which might result from their strong overexpression of BAX. Indeed, addition of recombinant BAX also sensitized V2^-/- MEFs to tBID. Thus, VDAC2 acts as a crucial component in mitochondrial apoptosis by allowing the mitochondrial recruitment of BAK, thereby controlling tBID-induced OMM permeabilization and cell death.