Conserved metabolic adaptation mechanisms in cancer cells and yeast against mitochondrial dysfunction indicate an additional role of aerobic glycolysis for cell survival

Eukaryotic cells primarily generate ATP through oxidative phosphorylation and substrate-level phosphorylation. Despite the superior efficiency of oxidative phosphorylation, eukaryotic cells often utilize both pathways as aerobic glycolysis even in the presence of oxygen. However, its role in cell survival remains poorly understood. In this study, aerobic glycolysis of the Warburg effect in breast cancer cells (MCF7) and the Crabtree effect in a laboratory strain of Saccharomyces cerevisiae (S288C) were compared following treatment with electron transport chain inhibitors, including FCCP, antimycin A, and oligomycin. MCF7 and S288C exhibited strikingly similar metabolic rewiring toward substrate-level phosphorylation against the inhibitor treatment, suggesting that mitochondrial oxidative phosphorylation and cytosolic substrate-level phosphorylation communicate through a common mechanism. Measurements of mitochondrial membrane potential (MMP) and ATP concentration further indicated that cytosolic ATP was transported into the mitochondria under conditions of reduced electron transport chain activity. This ATP was likely utilized by the reverse mode of H+/ATPase to maintain the MMP which contributed to avoiding programmed cell death. These results suggest that the ATP supply to mitochondria plays a conserved role in aerobic glycolysis across yeast and mammalian cancer cells. This mechanism likely contributes to cell survival under conditions of fluctuating oxygen availability.