4 May 2012
Alexander van Oudenaarden
Systems Biology Lab
Departments of Physics and Biology, MIT
Hubrecht Institute for Developmental Biology and Stem Cell Research
Utrecht, Holland
Since the pioneering work of Jacques Monod in 1941, the diauxic growth of bacteria or yeast, and especially the phase of exponential growth, has been a central experimental paradigm, which is used on a daily basis. Despite the historic familiarity of the diauxic growth, many aspects of cell growth and physiology during the diauxic growth have not been quantified. We quantified metabolic fluxes, oxygen consumption and carbon dioxide production during a full time-course of the diauxic growth of budding yeast and made two surprising discoveries. First, we find that during the exponential growth phase yeast cells can substantially change their metabolic state reflected in major changes in glucose uptake, respiration and fermentation even while the growth rate remained constant. These metabolic changes were reflected in major changes in gene expression, underscoring the observations that a constant growth rate does not necessarily indicate a steady-state growth and that cells can maintain a constant growth rate using very different metabolic strategies. Our second surprising discovery is the sign of the flux changes: as glucose was gradually depleted from the growth medium, a larger fraction of the glucose taken up by the cells was fermented to ethanol, and consistently the rate of oxygen consumption per cell decreased. These fluxes are in stark contrast with the current steady-state model assuming that the rate of fermentation is proportional to the glucose concentration and the rate of glucose uptake. Our results, taken together, demonstrate that quantification of the absolute rates of respiration and fermentation is essential to understanding cell growth and will help to characterize the trade-offs inherent to each metabolic strategy.