VDAC2 is required for truncated BID-induced mitochondrial apoptosis by recruiting BAK to the mitochondria

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.