The role of metabolic memory in the ATP paradox and energy homeostasis

In yeast, a sudden transition from glucose limitation to glucose excess leads to a new steady state at increased metabolic fluxes with a sustained decrease in the ATP concentration. Although this behaviour has been rationalized as an adaptive metabolic strategy, the mechanism behind it remains unclear. Nevertheless, it is thought that, on glucose addition, a metabolite derived from glycolysis may up-regulate ATP-consuming reactions. The adenine nucleotides themselves have been ruled out as the signals that mediate this regulation. This is mainly because, in that case, it would be expected that the new steady state at increased fluxes would be accompanied by an increased stationary ATP concentration. In this study, we present a core model consisting of a monocyclic interconvertible enzyme system. Using a supply-demand approach, we demonstrate that this system can account for the empirical observations without involving metabolites other than the adenine nucleotides as effectors. Moreover, memory is an emerging property of such a system, which may allow the cell to sense both the current energy status and the direction of the changes.