Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC

Nature. 1999 Jun 3;399(6735):483-7. doi: 10.1038/20959.


During transduction of an apoptotic (death) signal into the cell, there is an alteration in the permeability of the membranes of the cell's mitochondria, which causes the translocation of the apoptogenic protein cytochrome c into the cytoplasm, which in turn activates death-driving proteolytic proteins known as caspases. The Bcl-2 family of proteins, whose members may be anti-apoptotic or pro-apoptotic, regulates cell death by controlling this mitochondrial membrane permeability during apoptosis, but how that is achieved is unclear. Here we create liposomes that carry the mitochondrial porin channel (also called the voltage-dependent anion channel, or VDAC) to show that the recombinant pro-apoptotic proteins Bax and Bak accelerate the opening of VDAC, whereas the anti-apoptotic protein Bcl-x(L) closes VDAC by binding to it directly. Bax and Bak allow cytochrome c to pass through VDAC out of liposomes, but passage is prevented by Bcl-x(L). In agreement with this, VDAC1-deficient mitochondria from a mutant yeast did not exhibit a Bax/Bak-induced loss in membrane potential and cytochrome c release, both of which were inhibited by Bcl-x(L). Our results indicate that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cytochrome c Group / metabolism*
  • Humans
  • Intracellular Membranes / metabolism
  • Ion Channels / metabolism*
  • Liposomes
  • Membrane Potentials
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mitochondria / metabolism*
  • Mitochondria, Liver / metabolism
  • Mitochondrial ADP, ATP Translocases / metabolism
  • Porins / genetics
  • Porins / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Rats
  • Sucrose / metabolism
  • Voltage-Dependent Anion Channel 1
  • Voltage-Dependent Anion Channels
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • bcl-X Protein


  • BAK1 protein, human
  • BAX protein, human
  • BCL2L1 protein, human
  • Bak1 protein, rat
  • Bax protein, rat
  • Bcl2l1 protein, rat
  • Cytochrome c Group
  • Ion Channels
  • Liposomes
  • Membrane Proteins
  • Porins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • VDAC1 protein, human
  • Vdac1 protein, rat
  • Voltage-Dependent Anion Channels
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Sucrose
  • Mitochondrial ADP, ATP Translocases
  • Voltage-Dependent Anion Channel 1