Ph-Induced Oligomerization of the Voltage Dependent Anion Channel

Abstract

The Voltage-Dependent Anion Channel (VDAC) is the most abundant protein in the outer mitochondrial membrane facilitating the passage of ions and metabolites between the cytoplasm and the intermembrane space. In addition to its critical role in bioenergetics, VDAC is capable of modulating the organelle's permeability, implicating VDAC in metabolic stress and mitochondria-mediated apoptotic cell death. VDAC functions as a monomer but exhibits various oligomeric states, as shown by electron microscopy and atomic force microscopy. Oligomerization of VDAC can be linked to apoptosis and therefore is crucial for understanding mitochondrial regulation. Double Electron-Electron Resonance (DEER) on 4 singly spin-labeled mutants of mVDAC1 revealed a specific pH-induced dimerization. These inter-molecular distances were used to generate a model of a dimer interface that contains Glutamate 73. Mutation of Glutamate 73, to either Alanine or Glutamine, prevented pH induced oligomerization confirming the vital role of this residue. This dimer, induced by acidification, differs from any oligomeric form of VDAC previously described and likely plays a significant role in mitochondrial regulation and apoptosis in the response to cytosolic acidification during cellular stress.