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.

In eukaryotes, conserved mechanisms ensure that cell growth is coordinated with nutrient availability. Overactive growth during nutrient limitation leads to rapid cell death. Here, we demonstrate that cells can adapt to this nutrient-growth imbalance by evolving major metabolic defects. Specifically, when yeast lysine auxotrophic mutant lyssuffered nutrient-growth imbalance in limited lysine, a sub-population repeatedly evolved to lose the ability to synthesize organosulfurs (lys -orgS -). Organosulfurs, mainly glutathione and glutathione conjugates, were released by lyscells during lysine limitation when nutrientgrowth is imbalanced, but not during glucose limitation when nutrient-growth is balanced. Limiting organosulfurs conferred a frequency-dependent fitness advantage to lys -orgSby eliciting a proper slow growth program including autophagy. Thus, nutrient-growth imbalance can trigger rapid niche construction, which in turn enables the selection of an overt metabolic defect to better tune cell growth to the metabolic environment.