Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death

Nat Cell Biol. 2007 May;9(5):550-5. doi: 10.1038/ncb1575. Epub 2007 Apr 8.

Abstract

Mitochondria are critically involved in necrotic cell death induced by Ca(2+) overload, hypoxia and oxidative damage. The mitochondrial permeability transition (MPT) pore - a protein complex that spans both the outer and inner mitochondrial membranes - is considered the mediator of this event and has been hypothesized to minimally consist of the voltage-dependent anion channel (Vdac) in the outer membrane, the adenine-nucleotide translocase (Ant) in the inner membrane and cyclophilin-D in the matrix. Here, we report the effects of deletion of the three mammalian Vdac genes on mitochondrial-dependent cell death. Mitochondria from Vdac1-, Vdac3-, and Vdac1-Vdac3-null mice exhibited a Ca(2+)- and oxidative stress-induced MPT that was indistinguishable from wild-type mitochondria. Similarly, Ca(2+)- and oxidative-stress-induced MPT and cell death was unaltered, or even exacerbated, in fibroblasts lacking Vdac1, Vdac2, Vdac3, Vdac1-Vdac3 and Vdac1-Vdac2-Vdac3. Wild-type and Vdac-deficient mitochondria and cells also exhibited equivalent cytochrome c release, caspase cleavage and cell death in response to the pro-death Bcl-2 family members Bax and Bid. These results indicate that Vdacs are dispensable for both MPT and Bcl-2 family member-driven cell death.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Calcium / metabolism
  • Caspases / metabolism
  • Cell Death
  • Cell Membrane Permeability*
  • Cells, Cultured
  • Cyclophilin D
  • Cyclophilins / metabolism
  • Cytochromes c / metabolism
  • Mice
  • Mice, Knockout
  • Mitochondria, Heart / metabolism*
  • Mitochondria, Liver / metabolism*
  • Mitochondrial ADP, ATP Translocases / metabolism
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Membranes / metabolism*
  • Mitochondrial Proteins / metabolism
  • Mitochondrial Swelling
  • Oxidative Stress
  • Proto-Oncogene Proteins c-bcl-2
  • RNA Interference
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Time Factors
  • Transfection
  • Voltage-Dependent Anion Channel 1 / metabolism
  • Voltage-Dependent Anion Channel 2 / metabolism
  • Voltage-Dependent Anion Channels / deficiency
  • Voltage-Dependent Anion Channels / genetics
  • Voltage-Dependent Anion Channels / metabolism*

Substances

  • Cyclophilin D
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • PPIF protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Vdac1 protein, mouse
  • Vdac2 protein, mouse
  • Vdac3 protein, mouse
  • Voltage-Dependent Anion Channel 2
  • Voltage-Dependent Anion Channels
  • mitochondrial permeability transition pore
  • Cytochromes c
  • Mitochondrial ADP, ATP Translocases
  • Voltage-Dependent Anion Channel 1
  • Caspases
  • Cyclophilins
  • Calcium