Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria

J Cell Biol. 2002 Nov 25;159(4):613-24. doi: 10.1083/jcb.200205091. Epub 2002 Nov 18.


Although the physiological relevance of mitochondrial Ca2+ homeostasis is widely accepted, no information is yet available on the molecular identity of the proteins involved in this process. Here we analyzed the role of the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane in the transmission of Ca2+ signals between the ER and mitochondria by measuring cytosolic and organelle [Ca2+] with targeted aequorins and Ca2+-sensitive GFPs. In HeLa cells and skeletal myotubes, the transient expression of VDAC enhanced the amplitude of the agonist-dependent increases in mitochondrial matrix Ca2+ concentration by allowing the fast diffusion of Ca2+ from ER release sites to the inner mitochondrial membrane. Indeed, high speed imaging of mitochondrial and cytosolic [Ca2+] changes showed that the delay between the rises occurring in the two compartments is significantly shorter in VDAC-overexpressing cells. As to the functional consequences, VDAC-overexpressing cells are more susceptible to ceramide-induced cell death, thus confirming that mitochondrial Ca2+ uptake plays a key role in the process of apoptosis. These results reveal a novel function for the widely expressed VDAC channel, identifying it as a molecular component of the routes for Ca2+ transport across the mitochondrial membranes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Calcium / metabolism*
  • Cells, Cultured
  • Endoplasmic Reticulum / metabolism
  • Enzyme Inhibitors / metabolism
  • Fluorescent Dyes / metabolism
  • Fura-2 / analogs & derivatives*
  • Fura-2 / metabolism
  • HeLa Cells
  • Homeostasis
  • Humans
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Ion Transport
  • Mitochondria / metabolism*
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / metabolism
  • Porins / genetics
  • Porins / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2*
  • Rats
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Voltage-Dependent Anion Channels
  • bcl-2-Associated X Protein


  • Enzyme Inhibitors
  • Fluorescent Dyes
  • Ion Channels
  • N-acetylsphingosine
  • Porins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins
  • Voltage-Dependent Anion Channels
  • bcl-2-Associated X Protein
  • fura-2-am
  • Sphingosine
  • Calcium
  • Fura-2