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

EMBO Rep. 2009 Dec;10(12):1341-7. doi: 10.1038/embor.2009.219. Epub 2009 Oct 9.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • BH3 Interacting Domain Death Agonist Protein / genetics
  • BH3 Interacting Domain Death Agonist Protein / pharmacology*
  • Cells, Cultured
  • Drug Resistance / drug effects
  • Drug Resistance / genetics
  • Embryo, Mammalian
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Deletion
  • Gene Knockdown Techniques
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Membranes / metabolism
  • Permeability / drug effects
  • Protein Transport / drug effects
  • Recombinant Proteins / pharmacology
  • Voltage-Dependent Anion Channel 2 / genetics
  • Voltage-Dependent Anion Channel 2 / physiology*
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism*
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism
  • bcl-2-Associated X Protein / physiology


  • BH3 Interacting Domain Death Agonist Protein
  • Bak1 protein, mouse
  • Bid protein, mouse
  • Recombinant Proteins
  • Vdac2 protein, mouse
  • Voltage-Dependent Anion Channel 2
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein