The Warburg Effect as a VDAC‐Hexokinase‐Mediated Electrical Suppression of Mitochondrial Energy Metabolism

It is known that nearly half of tumor energy metabolism is provided by glycolysis under normal aerobic conditions (the Warburg Effect) that has been attributed to a respiratory impairment in cancer cells. In the last years, the mitochondrial impairment in cancer cells has been explained by the closure of mitochondrial outer membrane VDACs (porins) by free tubulin (as molecular corks) leading to a suppression of mitochondrial metabolism. Here, we further developed a concept that mitochondria in cancer cells are suppressed by the outer membrane potential (OMP) generated by the metabolically‐dependent mechanism involving the functioning of the VDAC‐hexokinase and/or the ANT(adenine nucleotide translocator)‐VDAC‐hexokinase complexes.These complexes and generated OMP allow initiation of glycolysis preferentially by ATP generated in mitochondria. High selectivity of channeling of mitochondrial energy into the cytosol of cancer cells, to only initiate glycolysis, is achieved due to the electrical closure of free VDACs (non‐bound to hexokinase) by the metabolically‐dependent OMP, by a mode preventing turbo acceleration of glycolysis by cytosolic ATP. Even at low values of OMP, not high enough to completely close VDACs, the ATP flux from the mitochondrial intermembrane space should be almost completely suppressed according to Goldman equation. The value of OMP directly generatedby the VDAC‐hexokinase complex, for example, depends on the Gibbs free energy of the hexokinase reaction. It means that VDAC might function as a physiologically important electrical switcher of tumor energy metabolism, allowing a clear explanation of the Warburg Effect mechanism. (Research grants #111852128625 and #520154531565, Colciencias).