Lost in Transition: Start-Up of Glycolysis Yields Subpopulations of Nongrowing Cells

TLDR

Cells must adapt to dynamic environments, and yeast that cannot cope with fluctuating glucose levels undergo growth arrest. Spontaneous, nongenetic metabolic variability among individual cells determines which glycolytic state is reached and thus which cells survive. Imbalanced glycolysis, a generic risk arising from its fundamental design, causes growth arrest in yeast, but transient ATP hydrolysis through futile cycling reduces this risk, demonstrating that metabolic heterogeneity alone can dictate cell fate.

Abstract

Cells need to adapt to dynamic environments. Yeast that fail to cope with dynamic changes in the abundance of glucose can undergo growth arrest. We show that this failure is caused by imbalanced reactions in glycolysis, the essential pathway in energy metabolism in most organisms. The imbalance arises largely from the fundamental design of glycolysis, making this state of glycolysis a generic risk. Cells with unbalanced glycolysis coexisted with vital cells. Spontaneous, nongenetic metabolic variability among individual cells determines which state is reached and, consequently, which cells survive. Transient ATP (adenosine 5'-triphosphate) hydrolysis through futile cycling reduces the probability of reaching the imbalanced state. Our results reveal dynamic behavior of glycolysis and indicate that cell fate can be determined by heterogeneity purely at the metabolic level.