Modulation of the mitochondrial voltage-dependent anion channel (VDAC) by hydrogen peroxide and its recovery by...

The Voltage-Dependent Anion Channel (VDAC) plays a vital role in mitochondria-mediated transport of ions and metabolites. It is well established that mitochondria are a site for production of hydrogen peroxide (H₂O₂). Excess production of H₂O₂ is toxic to the cell and causes oxidative stress. Therefore, the effect of H₂O₂ on the single-channel conductance of VDAC was investigated. In vitro bilayer electrophysiology experiments were performed on VDAC isolated from rat brain mitochondria, which consists predominately of the isoform VDAC1. VDAC was treated with H₂O₂ on a planar bilayer membrane (BLM). The conductance of VDAC increased upon H₂O₂ treatment, whereas the same concentration of H₂O₂ was unable to affect the BLM (without protein) over a long period of time. Subsequently, the sequential addition of curcumin to H₂O₂-treated VDAC reduced the conductance. Experimental results (bilayer electrophysiology) demonstrate the role of curcumin in the restoration of the activity of VDAC affected by H₂O₂. In silico docking studies enables identification of the probable binding site of H₂O₂ on VDAC. We further find that the oligomerization of VDAC that results in its increased conductance is an effect of lipid oxidation by H₂O₂.