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VDAC2 inhibits BAK activation and mitochondrial apoptosis.

The multidomain proapoptotic molecules BAK or BAX are required to initiate the mitochondrial pathway of apoptosis. How cells maintain the potentially lethal proapoptotic effector BAK in a monomeric inactive conformation at mitochondria is unknown. In viable cells, we found BAK complexed with mitochondrial outer-membrane protein VDAC2, a VDAC isoform present in low abundance that interacts specifically with the inactive conformer of BAK. Cells deficient in VDAC2, but not cells lacking the more abundant VDAC1, exhibited enhanced BAK oligomerization and were more susceptible to apoptotic death. Conversely, overexpression of VDAC2 selectively prevented BAK activation and inhibited the mitochondrial apoptotic pathway. Death signals activate "BH3-only" molecules such as tBID, BIM, or BAD, which displace VDAC2 from BAK, enabling homo-oligomerization of BAK and apoptosis. Thus, VDAC2, an isoform restricted to mammals, regulates the activity of BAK and provides a connection between mitochondrial physiology and the core apoptotic pathway.

Pubmed ID: 12881569


  • Cheng EH
  • Sheiko TV
  • Fisher JK
  • Craigen WJ
  • Korsmeyer SJ


Science (New York, N.Y.)

Publication Data

July 25, 2003

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS42319
  • Agency: NCI NIH HHS, Id: R37CA50239

Mesh Terms

  • Animals
  • Apoptosis
  • BH3 Interacting Domain Death Agonist Protein
  • Biopolymers
  • Carrier Proteins
  • Cell Line
  • Cells, Cultured
  • Etoposide
  • Humans
  • Intracellular Membranes
  • Jurkat Cells
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria
  • Mitochondria, Liver
  • Porins
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Proteins
  • Staurosporine
  • Voltage-Dependent Anion Channel 1
  • Voltage-Dependent Anion Channel 2
  • Voltage-Dependent Anion Channels
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein