Compounds toxic to stationary-phase yeast reveal a role for lipid metabolism in quiescent cell survival

The mechanisms that enable quiescent cells to survive nutrient-limited conditions remain imcompletely understood. To investigate these mechanisms, we performed a large-scale chemical screen to identify compounds that reduce viability of stationary-phase fission yeast cells. We identified two structurally related compounds that impair quiescent cell survival. In stationary phase, these compounds inhibited cell cycle re-entry, altered lipid droplets (LDs), and affected nuclear and chromosomal size, all of which are associated with lipid metabolism. In proliferating cells, they induced cell cycle arrest accompanied by nucleolar accumulation of cyclin-dependent kinase (CDK), a hallmark of stationary-phase cells, and inhibited mitochondrial oxygen consumption. The lipid synthesis inhibitor cerulenin similarly inhibited cell cycle re-entry and induced cell cycle arrest with nucleolar CDK accumulation; however, it did not reduce viability in stationary-phase cells or reproduce the other cellular effects. These results indicate that the compounds may affect lipid metabolism potentially by impairing lipid mobilization. Furthermore, the compounds were also toxic to stationary-phase budding yeast, suggesting conservation of survival mechanisms in quiescent cells. Together, our findings suggest that lipid metabolism, possibly lipid mobilization, plays a critical role in quiescent cell survival.