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Abstract
Metabolic behaviours of proliferating cells are often explained as a consequence of rational optimization of cellular growth rate, whereas microeconomics formulates consumption behaviours as optimization problems. Here, we pushed beyond the analogy to precisely map metabolism onto the theory of consumer choice. We thereby revealed the correspondence between long-standing mysteries in both fields: the Warburg effect, a seemingly wasteful but ubiquitous strategy where cells favour aerobic glycolysis over more energetically efficient oxidative phosphorylation, and Giffen behaviour, the unexpected consumer behaviour where a good is demanded more as its price rises. We identified the minimal, universal requirements for the Warburg effect: a trade-off between oxidative phosphorylation and aerobic glycolysis and complementarity, i.e. impossibility of substitution for different metabolites. Thus, various hypotheses for the Warburg effect are integrated into an identical optimization problem with the same universal structure. Besides, the correspondence between the Warburg effect and Giffen behaviour implies that oxidative phosphorylation is counter-intuitively stimulated when its efficiency is decreased by metabolic perturbations such as drug administration or mitochondrial dysfunction; the concept of Giffen behaviour bridges the Warburg effect and the reverse Warburg effect. This highlights that the application of microeconomics to metabolism can offer new predictions and paradigms for both biology and economics.
Highlights
Metabolic behaviours of proliferating cells can be often explained as a consequence of rational regulation to optimize cellular growth rate, as successfully predicted by biological theories such as flux balance analysis (FBA) (Bordbar et al 2014; Edwards et al 2001; Ibarra et al 2002; Schuetz et al 2012)
We consider a simple metabolic system that comprises the intake flux of the carbon source as a nutrient, JC,in, and fluxes to metabolize the nutrient to energy molecules in oxidative phosphorylation, JC,ox, and glycolytic pathways, JC,g (Fig. 1a)
By constructing a simplified utility landscape comprising only a few variables with the aid of microeconomics, we uncovered the minimal, universal requirements for the Warburg effect and Giffen behaviour: trade-off and complementarity, i.e. impossibility of substitution for different goods. It no longer depends on the specific assumption of limited resource allocation (“Appendix 2”). Such extraction of the essence of the Warburg effect by microeconomic concepts offers a novel theory for the reverse Warburg effect induced by the uncoupler administration or mitochondrial dysfunction
Summary
Metabolic behaviours of proliferating cells can be often explained as a consequence of rational regulation to optimize cellular growth rate, as successfully predicted by biological theories such as flux balance analysis (FBA) (Bordbar et al 2014; Edwards et al 2001; Ibarra et al 2002; Schuetz et al 2012). Giffen behaviour represents the counter-intuitive phenomenon in microeconomics, where the demand for a good increases when its price rises.
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