Anti‐cancer drugs targeting the NADH ‐binding site of VDAC rewire channel electrophysiology and partially suppress cation selectivity

Located at the crossroads between mitochondria and cytosol, VDAC1 (Voltage-Dependent Anion Selective Channel isoform 1) serves as the chief actor in the regulation of cell metabolism and apoptosis. The crucial role in cell fate determination has long made VDAC1 a promising target in cancer research. The recent discovery of a highly conserved and druggable NADH-like binding pocket has led to the development of specific VDAC antagonists (VA) with potential antitumor activity. Here, we performed electrophysiological analysis in artificial lipid membranes to examine in detail how these drugs affect VDAC1 gating. Upon addition of VA molecules to a planar bilayer containing recombinant human VDAC1, single channel recordings showed a reliable reduction in the voltage dependence of the pore. Experiments performed in asymmetric KCl solution revealed that VA binding renders the channel predominantly anion selective, potentially disrupting cation fluxes and simultaneously affecting the transport of negatively charged metabolites. Taken together, these data represent a step forward into the comprehension of VDAC modulation as a potential therapeutic approach in cancer management.