Voltage-dependent anion channels modulate mitochondrial metabolism in cancer cells: regulation by free tubulin and erastin

J Biol Chem. 2013 Apr 26;288(17):11920-9. doi: 10.1074/jbc.M112.433847. Epub 2013 Mar 7.

Abstract

Respiratory substrates and adenine nucleotides cross the mitochondrial outer membrane through the voltage-dependent anion channel (VDAC), comprising three isoforms--VDAC1, 2, and 3. We characterized the role of individual isoforms in mitochondrial metabolism by HepG2 human hepatoma cells using siRNA. With VDAC3 to the greatest extent, all VDAC isoforms contributed to the maintenance of mitochondrial membrane potential, but only VDAC3 knockdown decreased ATP, ADP, NAD(P)H, and mitochondrial redox state. Cells expressing predominantly VDAC3 were least sensitive to depolarization induced by increased free tubulin. In planar lipid bilayers, free tubulin inhibited VDAC1 and VDAC2 but not VDAC3. Erastin, a compound that interacts with VDAC, blocked and reversed mitochondrial depolarization after microtubule destabilizers in intact cells and antagonized tubulin-induced VDAC blockage in planar bilayers. In conclusion, free tubulin inhibits VDAC1/2 and limits mitochondrial metabolism in HepG2 cells, contributing to the Warburg phenomenon. Reversal of tubulin-VDAC interaction by erastin antagonizes Warburg metabolism and restores oxidative mitochondrial metabolism.

Publication types

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

MeSH terms

  • Adenosine Diphosphate / genetics
  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / genetics
  • Adenosine Triphosphate / metabolism
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Gene Knockdown Techniques
  • Hep G2 Cells
  • Humans
  • Lipid Bilayers / metabolism
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • NADP / genetics
  • NADP / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Oxidation-Reduction
  • Piperazines / pharmacology*
  • Tubulin / metabolism*
  • Voltage-Dependent Anion Channels / genetics
  • Voltage-Dependent Anion Channels / metabolism*

Substances

  • Lipid Bilayers
  • Mitochondrial Proteins
  • Neoplasm Proteins
  • Piperazines
  • Tubulin
  • Voltage-Dependent Anion Channels
  • erastin
  • NADP
  • Adenosine Diphosphate
  • Adenosine Triphosphate