Voltage Dependent Anion Channels, ATP/ADP Exchange and Warburg Metabolism
High rates of aerobic glycolysis and suppression of mitochondrial metabolism characterize the Warburg metabolic phenotype of cancer cells. During mitochondrial metabolism, hydrophilic metabolites like ATP, ADP, Pi and respiratory substrates enter and exit mitochondria through voltage-dependent anion channels (VDAC) in the mitochondrial outer membrane. Previously considered to be constitutively open, emerging data shows that VDAC is an adjustable limiter (governator) of mitochondrial metabolic flux. Rostovtseva and coworkers first showed that unpolymerized heterodimeric tubulin inhibits conductance of VDAC reconstituted into planar lipid bilayers. In tumor cells, high cytoplasmic free tubulin also inhibits mitochondrial metabolism and membrane potential (ΔΨ) generation. Cancer cells express three VDAC isoforms, and knockdown studies show that tubulin inhibits VDAC1 and VDAC2 but not the less abundant VDAC3. When spindles form as proliferating cells enter metaphase, free tubulin decreases, and VDAC may open to better provide for the high ATP demands of cell division. In aerobic post-mitotic cells like cardiac myocytes and hepatocytes, high cytosolic ATP/ADP ratios (up to 100 times greater than mitochondrial matrix ATP/ADP) is made possible by the electrogenic adenine nucleotide translocator (ANT) in the mitochondrial inner membrane, which exports ATP4- in exchange for cytosolic ADP3- driven by ΔΨ. However in proliferating cancer cells, recent studies support the conclusion that non-electrogenic ATP/ADP exchange, possibly catalyzed by the ATP/Mg-Pi carrier, replaces electrogenic ANT exchange. We propose that relative closure of VDAC by tubulin together with non-electrogenic ATP/ADP exchange contributes to lower cytosolic ATP/ADP ratios, activation of aerobic glycolysis and a Warburg metabolic phenotype in proliferating cells.