Regulation of Eukaryote Metabolism: An Abstract Model Explaining the Warburg/Crabtree Effect

Abstract

Adaptation of metabolism is a response of many eukaryotic cells to nutrient heterogeneity in the cell microenvironment. One of these adaptations is the shift from respiratory to fermentative metabolism, also called the Warburg/Crabtree effect. It is a response to a very high nutrient increase in the cell microenvironment, even in the presence of oxygen. Understanding whether this metabolic transition can result from basic regulation signals between components of the central carbon metabolism are the the core question of this work. We use an extension of the René Thomas modeling framework for representing the regulations between the main catabolic and anabolic pathways of eukaryotic cells, and formal methods for confronting models with known biological properties in different microenvironments. The formal model of the regulation of eukaryote metabolism defined and validated here reveals the conditions under which this metabolic phenotype switch occurs. It clearly proves that currently known regulating signals within the main components of central carbon metabolism can be sufficient to bring out the Warburg/Crabtree effect. Moreover, this model offers a general perspective of the regulation of the central carbon metabolism that can be used to study other biological questions.