UC Berkeley

Many prokaryotic and eukaryotic cells metabolize glucose to organism-specific byproducts instead of fully oxidizing it to carbon dioxide and water–a phenomenon referred to as the Warburg Effect. The benefit to a cell is not fully understood, given that partial metabolism of glucose yields an order of magnitude less ATP per molecule of glucose than complete oxidation. Here, we test a previously formulated hypothesis that the benefit of the Warburg Effect is to increase ATP production rate by switching from high-yielding respiration to faster glycolysis when excess glucose is available and respiration rate becomes limited by proteome occupancy. We show that glycolysis produces ATP faster per gram of pathway protein than respiration in E. coli, S. cerevisiae, and mammalian cells. We then develop a simple mathematical model of energy metabolism that uses five experimentally estimated parameters and show that this model can accurately predict absolute rates of glycolysis and respiration in all three organisms under diverse conditions, providing strong support for the validity of the ATP production rate maximization hypothesis. In addition, our measurements show that mammalian respiration produces ATP up to 10-fold slower than respiration in E. coli or S. cerevisiae, suggesting that the ATP production rate per gram of pathway protein is a highly evolvable trait that is heavily optimized in microbes. We also find that E. coli respiration is faster than fermentation, explaining the observation that E. coli, unlike S. cerevisiae or mammalian cells, never switch to pure fermentation in the presence of oxygen.Glycolytic ATP production is critical for meeting the high energy demands of rapidly proliferating cells. We establish a strong linear correlation between ATP production rates and cellular growth across diverse organisms, including E. coli, S. cerevisiae, and mammalian cells. We found that glycolysis can fully compensate for the inhibition of respiration, whereas the respiratory pathway is insufficient to meet ATP demands when glycolysis is inhibited. When glycolytic ATP production is lost, cell growth slows, demonstrating the necessity of glycolysis in sustaining fast growth. Furthermore, we investigate how cells dynamically adjust their metabolic preferences in response to altered ATP demands by using cycloheximide to inhibit protein synthesis. This treatment uncovers a remarkable flexibility in energy metabolism, with cells shifting between glycolysis and respiration to optimize ATP production under varying conditions. Our findings uncover the indispensable role of glycolysis in facilitating rapid proliferation. This work provides novel insights into the mechanisms the metabolic flexibility of ATP production.