Translational antagonism enables bet-hedging in yeast via mitochondrial bistability

Abstract

We investigated the molecular basis of bet-hedging in budding yeast, Saccharomyces cerevisiae. Fast glycolytic growth generates two cell states: fermenting arrestors and respiring recoverers, of which only recoverers resume growth when shifted to a respiratory carbon source. Single-cell metabolic biosensors show that a bistable switch in mitochondrial activity produces these states: mitochondrial membrane potential drives import of positively charged, nuclear-encoded proteins of the mitochondrial ribosome, and mitochondrial ribosomes synthesize electron transport chain subunits that sustain the potential, completing a positive feedback loop. The ratio of mitochondrial to cytoplasmic protein synthesis governs switch dynamics: the effect of slowing mitochondrial translation is rescued by inhibiting cytosolic translation. Reducing mitochondrial translation reconstitutes bistability in evolutionarily distant fission yeast, suggesting a conserved mechanism for diversifying single-cell ATP production strategies.