Key regions of VDAC1 functioning in apoptosis induction and regulation by hexokinase

Biochim Biophys Acta. 2009 May;1787(5):421-30. doi: 10.1016/j.bbabio.2008.11.009. Epub 2008 Nov 27.


The voltage-dependent anion channel (VDAC), located in the mitochondrial outer membrane, functions as gatekeeper for the entry and exit of mitochondrial metabolites, and thus controls cross-talk between mitochondria and the cytosol. VDAC also serves as a site for the docking of cytosolic proteins, such as hexokinase, and is recognized as a key protein in mitochondria-mediated apoptosis. The role of VDAC in apoptosis has emerged from various studies showing its involvement in cytochrome c release and apoptotic cell death as well as its interaction with proteins regulating apoptosis, including the mitochondria-bound isoforms of hexokinase (HK-I, HK-II). Recently, the functional HK-VDAC association has shifted from being considered in a predominantly metabolic light to the recognition of its major impact on the regulation of apoptotic responsiveness of the cell. Here, we demonstrate that the HK-VDAC1 interaction can be disrupted by mutating VDAC1 and by VDAC1-based peptides, consequently leading to diminished HK anti-apoptotic activity, suggesting that disruption of HK binding to VDAC1 can decrease tumor cell survival. Indeed, understanding structure-function relationships of VDAC is critical for deciphering how this channel can perform such a variety of differing functions, all important for cell life and death. By expressing VDAC1 mutants and VDAC1-based peptides, we have identified VDAC1 amino acid residues and domains important for interaction with HK and protection against apoptosis. These include negatively- and positively-charged residues, some of which are located within beta-strands of the protein. The N-terminal region of VDAC1 binds HK-I and prevents HK-mediated protection against apoptosis induced by STS, while expression of a VDAC N-terminal peptide detaches HK-I-GFP from mitochondria. These findings indicate that the interaction of HK with VDAC1 involves charged residues in several beta-strands and in the N-terminal domain. Displacing HK, serving as the 'guardian of the mitochondrion', from its binding site on VDAC1 may thus be exploited as an approach to cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Breast Neoplasms
  • Cell Line
  • Cell Line, Tumor
  • Female
  • HeLa Cells
  • Hexokinase / metabolism*
  • Homeostasis
  • Humans
  • Ion Channels / physiology
  • Kidney
  • Kinetics
  • Transfection
  • U937 Cells
  • Voltage-Dependent Anion Channel 1 / chemistry
  • Voltage-Dependent Anion Channel 1 / genetics
  • Voltage-Dependent Anion Channel 1 / physiology*


  • Ion Channels
  • VDAC1 protein, human
  • Voltage-Dependent Anion Channel 1
  • Hexokinase