PNNL

Abstract

Metabolic trade-offs between growth and productivity are key constraints in metabolic engineering and adaptive evolution; however, how cellular noise impacts these trade offs and drives the emergence of subpopulations with distinct resource allocation strategies, remains largely unknown. Here, we introduce a single-cell strategy for quantifying the trade-offs between triacylglycerol production and growth in the oleaginous microorganism Yarrowia lipolytica. The strategy relies on high-throughput quantitative-phase imaging and, enabled by nanoscale secondary ion mass spectrometry analyses and dedicated image processing, allows us to image how resources are partitioned between growth and productivity. Enhanced precision over population-averaging biotechnologies and conventional microscopy demonstrates how cellular noise impacts growth and productivity differently. As such, subpopulations with distinct metabolic trade-offs emerge, with notable impacts on strain performance and robustness. By quantifying autophagic catabolic fluxes under nutrient-limiting conditions, we discover an underlying cell-to-cell heterogeneity in protein and fatty-acid recycling, unmasking a potential bet-hedging survival strategy under starvation.