SP17 Warburg effect

SP17 Modelling the Warburg effect in healthy cells

Project leader: Stefan Schuster

Background and previous work
For producing ATP, tumour cells rely on glycolysis (rather than on respiration) to a significantly higher extent than the corresponding healthy cells. This is known as the Warburg effect. In the context of the RTG, it is of interest that also in healthy cells of various types, mild stress leads to an upregulation of glycolysis. For example, lymphocytes show this effect upon stimulation by antigens or mitogens, and so do microglia and Kupffer cells upon stimulation by, for example, endotoxins. This metabolic behaviour is closely related to tolerance and resistance. High glycolytic rates even under normal conditions are found in several other cell types, such as endothelial cells, stem cells and red blood cells. Various molecular causes for the Warburg effect have been proposed in the literature: lack of oxygen, increased ATP production rate, increased precursor synthesis and others. The Warburg effect is paradoxical at first sight because the ATP-versus-glucose yield of glycolysis is lower than that of respiration. On the other hand, glycolysis can reach much higher ATP production rates, which leads, from a game-theoretical viewpoint, to a "Tragedy of the Commons". Recently, we established a minimalist mathematical model for explaining the Warburg effect, which is much easier to use than the complex model proposed by.

Specific aims and working programme
After fitting the parameters to experimental data provided by the partner groups, our general mathematical model of the Warburg effect will be used as a basis for analysing several cell types. In particular, we will study quantitatively the metabolic switch under mild stress in microglia cells, several subtypes of lymphocytes and in endothelial cells. The energy metabolism of lymphocytes under various special conditions such as fungal infections and sepsis will be simulated by computer. A constraint on oxygen availability will be included to model hypoxic conditions such as for immune cells entering tumours. In the next step, we will establish a novel model in which the conversion between pyruvate and lactate is considered reversible. This concerns cells that take up lactate and use it for respiration, such as neurons. The modelling and computer simulations will be used to make testable predictions on hormetic effects, increased ATP production rate, glucose depletion, the effect of hypoxic conditions etc., in view of medical applications.