Self-organizing glycolytic waves tune cellular metabolic states and fuel cancer progression

Abstract

Abstract Although glycolysis is traditionally considered a cytosolic reaction, here we show that glycolytic enzymes propagate as self-organized waves on the membrane/cortex of human cells. Altering these waves led to corresponding changes in glycolytic activity, ATP production, and dynamic cell behaviors, impacting energy-intensive processes such as macropinocytosis and protein synthesis. Mitochondria were absent from the waves, and inhibiting oxidative phosphorylation (OXPHOS) had minimal effect on ATP levels or cellular dynamics. Synthetic membrane recruitment of individual glycolytic enzymes increased cell motility and co-recruited additional enzymes, suggesting assembly of glycolytic multi-enzyme complexes in the waves. Remarkably, wave activity and glycolytic ATP levels increased in parallel across human mammary epithelial and other cancer cell lines with higher metastatic potential. Cells with stronger wave activity relied more on glycolysis than on OXPHOS for ATP. These results reveal a distinct subcellular compartment for enriched local glycolysis at the cell periphery and suggest a mechanism that coordinates energy production with cellular state, potentially explaining the Warburg effect.