Overflow metabolism originates from growth optimization and cell heterogeneity

• Published in: eLife Vol. 13
• Main Author: Wang, Xin
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 05.06.2025; eLife Sciences Publications, Ltd
• Subjects: aerobic glycolysis; Biomass; Biosynthesis; Cancer; Carbon; Cell growth; cell heterogeneity; Cell Proliferation; Computational and Systems Biology; E coli; Energy consumption; Energy Metabolism; Enzyme kinetics; Escherichia coli - growth & development; Escherichia coli - metabolism; Fermentation; metabolic strategy; Metabolism; Metabolites; Models, Biological; overflow metabolism; Oxygen - metabolism; Physics of Living Systems; Proteins; Respiration; Saccharomyces cerevisiae - growth & development; Saccharomyces cerevisiae - metabolism; warburg effect; computational biology; systems biology; mouse; cell heterogeneity; I. orientalis; overflow metabolism; warburg effect; metabolic strategy; aerobic glycolysis; physics of living systems; E. coli; S. cerevisiae
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.94586

A classic problem in metabolism is that fast-proliferating cells use seemingly wasteful fermentation for energy biogenesis in the presence of sufficient oxygen. This counterintuitive phenomenon, known as overflow metabolism or the Warburg effect, is universal across various organisms. Despite extensive research, its origin and function remain unclear. Here, we show that overflow metabolism can be understood through growth optimization combined with cell heterogeneity. A model of optimal protein allocation, coupled with heterogeneity in enzyme catalytic rates among cells, quantitatively explains why and how cells choose between respiration and fermentation under different nutrient conditions. Our model quantitatively illustrates the growth rate dependence of fermentation flux and enzyme allocation under various perturbations and is fully validated by experimental results in Escherichia coli . Our work provides a quantitative explanation for the Crabtree effect in yeast and the Warburg effect in cancer cells and can be broadly used to address heterogeneity-related challenges in metabolism.