Reversible dissociation of mitochondrial Complex V balances anabolic and energy-generating needs in cancer

Cancer cell metabolic re-programming provides the additional energy and anabolic precursors necessary to sustain unregulated proliferation. This is partially mediated by the Warburg effect, which generates ATP while oxidizing glucose to a subset of these anabolites. Concurrently, mitochondrial mass and ATP generation via oxidative phosphorylation decline in most tumors. This raises the question of how increased glycolysis-derived anabolites can be balanced with those supplied by the TCA cycle. Using primary murine liver cancers and their derivative cell lines, we show that this can be explained by the dissociation of mitochondrial Complex V (CV or ATP synthase) into its component and functionally independent F_o and F₁ domains. This occurs as a result of marked declines in MT-ATP6, a CV subunit that stabilizes F_o-F₁ assembly. Serving as a proton pore, free F_o maintains a normal mitochondrial membrane potential without generating ATP, thus allowing the TCA cycle, electron transport chain, and anaplerotic reactions to function at high levels. Concurrently, free F₁ functions in reverse as an ATPase to limit excess ATP accumulation. The uncoupling of TCA-cycle-derived anabolic substrate production from membrane hyperpolarization and ATP overproduction by a smaller population of highly efficient mitochondria allows TCA-cycle-generated anabolic precursors to match those generated via glycolysis.