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.

在真核生物中，保守机制确保细胞生长与营养供应相协调。营养受限期间过度活跃的生长（“营养生长失调”）会导致细胞快速死亡。在这里，我们证明细胞可以通过发展主要代谢缺陷来适应营养生长失调。具体来说，当酵母赖氨酸营养缺陷型突变体lys ^-遇到赖氨酸限制（一种进化上新的压力）时，细胞会出现营养生长失调。一个亚群反复进化失去合成有机硫的能力（lys ^- orgS ^-）。lys释放有机硫，主要是还原型谷胱甘肽 (GSH) 和 GSH 结合物^-当生长失调时，赖氨酸限制期间的细胞，但当生长受到调节时，葡萄糖限制期间则没有。通过引发适当的缓慢生长程序，包括自噬，限制有机硫赋予lys ^- orgS ^{-频率依赖的适应性优势。}因此，营养生长失调与有机硫的快速释放有关，这使得有机硫营养缺陷的选择能够更好地调节细胞生长以适应代谢环境。我们推测进化上新的压力可以触发某些代谢物的非典型释放，为新的生态相互作用的进化奠定了基础。