Metabolic excretion associated with nutrient–growth dysregulation promotes the rapid evolution of an overt metabolic defect

In eukaryotes, conserved mechanisms ensure that cell growth is coordinated with nutrient availability. Overactive growth during nutrient limitation (“nutrient–growth dysregulation”) can lead to rapid cell death. Here, we demonstrate that cells can adapt to nutrient–growth dysregulation by evolving major metabolic defects. Specifically, when yeast lysine-auxotrophic mutant lys⁻ encountered lysine limitation, an evolutionarily novel stress, cells suffered nutrient–growth dysregulation. A subpopulation repeatedly evolved to lose the ability to synthesize organosulfurs (lys⁻orgS⁻). Organosulfurs, mainly reduced glutathione (GSH) and GSH conjugates, were released by lys⁻ cells during lysine limitation when growth was dysregulated, but not during glucose limitation when growth was regulated. Limiting organosulfurs conferred a frequency-dependent fitness advantage to lys⁻orgS⁻ by eliciting a proper slow growth program, including autophagy. Thus, nutrient–growth dysregulation is associated with rapid organosulfur release, which enables the selection of organosulfur auxotrophy to better tune cell growth to the metabolic environment. We speculate that evolutionarily novel stresses can trigger atypical release of certain metabolites, setting the stage for the evolution of new ecological interactions.