Selection for rapid uptake of scarce or fluctuating resource explains vulnerability of glycolysis to imbalance

Glycolysis is a conserved central pathway in energy metabolism that converts glucose to pyruvate with net production of two ATP molecules. Because ATP is produced only in the lower part of glycolysis (LG), preceded by an initial investment of ATP in the upper glycolysis (UG), achieving robust start-up of the pathway upon activation presents a challenge: a sudden increase in glucose concentration can throw a cell into a self-sustaining imbalanced state in which UG outpaces LG, glycolytic intermediates accumulate and the cell is unable to maintain high ATP concentration needed to support cellular functions. Such metabolic imbalance can result in “substrate-accelerated death”, a phenomenon observed in prokaryotes and eukaryotes when cells are exposed to an excess of substrate that previously limited growth. Here, we address why evolution has apparently not eliminated such a costly vulnerability and propose that it is a manifestation of an evolutionary trade-off, whereby the glycolysis pathway is adapted to quickly secure scarce or fluctuating resource at the expense of vulnerability in an environment with ample resource. To corroborate this idea, we perform individual-based eco-evolutionary simulations of a simplified yeast glycolysis pathway consisting of UG, LG, phosphate transport between a vacuole and a cytosol, and a general ATP demand reaction. The pathway is evolved in constant or fluctuating resource environments by allowing mutations that affect the (maximum) reaction rate constants, reflecting changing expression levels of different glycolytic enzymes. We demonstrate that under limited constant resource, populations evolve to a genotype that exhibits balanced dynamics in the environment it evolved in, but strongly imbalanced dynamics under ample resource conditions. Furthermore, when resource availability is fluctuating, imbalanced dynamics confers a fitness advantage over balanced dynamics: when glucose is abundant, imbalanced pathways can quickly accumulate the glycolytic intermediate FBP as intracellular storage that is used during periods of starvation to maintain high ATP concentration needed for growth. Our model further predicts that in fluctuating environments, competition for glucose can result in stable coexistence of balanced and imbalanced cells, as well as repeated cycles of population crashes and recoveries that depend on such polymorphism. Overall, we demonstrate the importance of ecological and evolutionary arguments for understanding seemingly maladaptive aspects of cellular metabolism.
Author summary Glycolysis is a central pathway in cellular energy metabolism that breaks down glucose to produce ATP, yet it can sometimes fail to start up properly after cells have experienced a period of starvation. This puzzling failure occurs when a sudden increase in glucose concentration throws a cell into a self-sustaining imbalanced state in which upper and lower glycolysis work at different rates. As a result, glycolytic intermediates accumulate in the cell, and it is unable to maintain high ATP concentration needed to support cellular functions. Here, we perform individual-based eco-evolutionary simulations of a simplified yeast glycolysis pathway and show that this apparently costly vulnerability allows for faster growth in environments with scarce or fluctuating resource availability. Accordingly, we propose that vulnerability to metabolic imbalance can be interpreted as a manifestation of an evolutionary trade-off between performance in rich, stable environments and poor, fluctuating ones. Furthermore, we show that when resource availability fluctuates, imbalanced dynamics itself can be advantageous: when glucose is abundant, imbalanced pathways can quickly accumulate glycolytic intermediates as intracellular storage that is used to sustain growth during periods of starvation. Finally, we find that in variable environments, competition for glucose can support stable coexistence of balanced and imbalanced cells in the population, as well as repeated cycles of population crashes and recoveries. Overall, our results show that ecological and evolutionary mechanisms provide a fruitful context for interpreting seemingly flawed aspects of cellular metabolism.