A modular model integrating metabolism, growth, and cell cycle predicts that fermentation is required to modulate cell size in yeast populations

by Marco Vanoni, Pasquale Palumbo, Federico Papa, Stefano Busti, Laura Gotti, Meike Wortel, Bas Teusink, Ivan Orlandi, Alex Pessina, Cristina Airoldi, Luca Brambilla, Marina Vai, Lilia Alberghina

For unicellular organisms, the reproduction rate and growth are crucial fitness determinants and functional manifestations of the organism genotype. Using the budding yeast Saccharomyces cerevisiae as a model organism, we integrated metabolism, which provides energy and building blocks for growth, with cell mass growth and cell cycle progression into a low-granularity, multiscale (from cell to population) computational model. This model predicted that cells with constitutive respiration do not modulate cell size according to the growth conditions. We experimentally validated the model predictions using mutants with defects in the upper part of glycolysis or glucose transport. Plugging in molecular details of cellular subsystems allowed us to refine predictions from the cellular to the molecular level. Our hybrid multiscale modeling approach provides a framework for structuring molecular knowledge and predicting cell phenotypes under various genetic and environmental conditions.