Voltage-Dependent Anion Channels and Tubulin: Bioenergetic Controllers in Cancer Cells

Abstract

The Warburg phenotype is characterized by enhanced glycolysis and suppression of mitochondrial metabolism. Sustained glycolysis depends on a low cytosolic ATP/ADP ratio that, in turn, occurs when mitochondrial metabolism is decreased. We propose that the voltage-dependent anion channel (VDAC) is a global controller of cancer cell bioenergetics. VDAC located in the mitochondrial outer membrane allows the flux of respiratory substrates, ADP, and Pi into mitochondria and the release of mitochondrial ATP to the cytosol. The tricarboxylic acid cycle generates NADH from the oxidation of respiratory substrates. NADH enters the respiratory chain to generate a proton motive force that maintains mitochondrial membrane potential (ΔΨ) and is utilized to generate ATP. The respiratory chain is also the major cellular source of mitochondrial reactive oxygen species (ROS). α-β tubulin heterodimers decrease VDAC conductance in lipid bilayers. Free tubulin by closing VDAC limits the ingress of respiratory substrates and ATP, thereby decreasing mitochondrial ΔΨ in tumor cells. By this mechanism, fluctuations of free tubulin dynamically regulate VDAC conductance and globally control mitochondrial metabolism, the intracellular flow of energy, and ROS formation. Erastin, a VDAC-binding molecule lethal to certain types of cancer cells, and erastin-like compounds identified in a small molecule screening antagonize the inhibitory effect of tubulin on VDAC. Blockage of tubulin inhibition of VDAC opens the channel to increase mitochondrial metabolism and subsequently decrease glycolysis. Mitochondrial hyperpolarization after VDAC opening also leads to oxidative stress and mitochondrial dysfunction, bioenergetic failure, and cell death. In summary, antagonism of VDAC-tubulin interaction promotes cell death by a “double hit model” characterized by reversion of the pro-proliferative Warburg phenotype and promotion of oxidative stress.