title: VDAC2 is required for truncated BID-induced mitochondrial apoptosis by recruiting BAK to the mitochondria.
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.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Suite 261 JAH, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Soumya Sinha
authors.initials: SS
authors.lastname: Roy
authors.forename: Amy M
authors.initials: AM
authors.lastname: Ehrlich
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.forename: György
authors.initials: G
authors.lastname: Hajnóczky
mesh_terms: 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
chemical_list: 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