The life cycle of microorganisms is associated with dynamic metabolic transitions and complex cellular responses. In yeast, how metabolic signals control the progressive choreography of structural reorganizations observed in quiescent cells during a natural life cycle remains unclear. We have developed an integrated microfluidic device to address this question, enabling continuous single-cell tracking in a batch culture experiencing unperturbed nutrient exhaustion to unravel the coordination between metabolic and structural transitions within cells. Our technique reveals an abrupt fate divergence in the population, whereby a fraction of cells is unable to transition to respiratory metabolism and undergoes a reversible entry into a quiescence-like state leading to premature cell death. Further observations reveal that nonmonotonous internal pH fluctuations in respiration-competent cells orchestrate the successive waves of protein superassemblies formation that accompany the entry into a bona fide quiescent state. This ultimately leads to an abrupt cytosolic glass transition that occurs stochastically long after proliferation cessation. This new experimental framework provides a unique way to track single-cell fate dynamics over a long timescale in a population of cells that continuously modify their ecological niche.
The life cycle of microorganisms is associated with dynamic metabolic transitions and complex cellular responses. In yeast, how metabolic signals control the progressive establishment of structural reorganizations observed in quiescent cells remains unclear. To address this question, we have developed a method that combines nutrient-limited proliferation assays at the population level with single-cell tracking to unravel the coordination between metabolic and structural transitions in cells during an unperturbed lifecycle. We show that non-monotonous internal pH fluctuations are in sync with successive waves of protein super-assemblies formation and ultimately lead to a cytosolic glass transition. Our results, therefore, suggest a simple model explaining how the complex developmental changes during the yeast life cycle are orchestrated by the sequence of metabolic transitions.
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