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.
Roy
Soumya Sinha
SS
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Suite 261 JAH, Philadelphia, Pennsylvania 19107, USA.
Ehrlich
Amy M
AM
Craigen
William J
WJ
Hajnóczky
György
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000494:pharmacology*; D002478:Cells, Cultured; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D050996:Voltage-Dependent Anion Channel 2 / Q000235:genetics / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D051023:BH3 Interacting Domain Death Agonist Protein; C494773:Bak1 protein, mouse; C494815:Bid protein, mouse; D011994:Recombinant Proteins; C494766:Vdac2 protein, mouse; D050996:Voltage-Dependent Anion Channel 2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein