A long-standing observation is that in fast-growing cells, respiration rate declines with increasing growth rate and is compensated by an increase in fermentation, despite respiration being more efficient than fermentation. This apparent preference for fermentation even in the presence of oxygen is known as aerobic glycolysis, and occurs in bacteria, yeast, and cancer cells. Considerable work has focused on understanding the potential benefits that might justify this seemingly wasteful metabolic strategy, but its mechanistic basis remains unclear. Here we show that aerobic glycolysis results from the saturation of mitochondrial respiration and the decoupling of mitochondrial biogenesis from the production of other cellular components. Respiration rate is insensitive to acute perturbations of cellular energetic demands or nutrient supplies, and is explained simply by the amount of mitochondria per cell. Mitochondria accumulate at a nearly constant rate across different growth conditions, resulting in mitochondrial amount being largely determined by cell division time. In contrast, glucose uptake rate is not saturated, and is accurately predicted by the abundances and affinities of glucose transporters. Combining these models of glucose uptake and respiration provides a quantitative, mechanistic explanation for aerobic glycolysis. The robustness of specific respiration rate and mitochondrial biogenesis, paired with the flexibility of other bioenergetic and biosynthetic fluxes, may play a broad role in shaping eukaryotic cell metabolism.

Robustness of mitochondrial biogenesis and respiration explain aerobic glycolysis