The role of glycolysis-derived hexose phosphates in the induction of the Crabtree effect

Mónica Rosas Lemus,Elodie Roussarie,Noureddine Hammad,Alexis Mougeolle,Stéphane Ransac,Razanne Issa,Jean-Pierre Mazat,Salvador Uribe-Carvajal,Michel Rigoulet,Anne Devin

doi:10.1074/jbc.ra118.003672

Abstract

Evidence for the Crabtree effect was first reported by H. Crabtree in 1929 and is defined as the glucose-induced decrease of cellular respiratory flux. This effect was observed in tumor cells and was not detected in most non-tumor cells. A number of hypotheses on the mechanism underlying the Crabtree effect have been formulated. However, to this day, no consensual mechanism for this effect has been described. In a previous study on isolated mitochondria, we have proposed that fructose-1,6-bisphosphate (F1,6bP), which inhibits the respiratory chain, induces the Crabtree effect. Using whole cells from the yeast Saccharomyces cerevisiae as a model, we show here not only that F1,6bP plays a key role in the process but that glucose-6-phosphate (G6P), a hexose that has an effect opposite to that of F1,6bP on the regulation of the respiratory flux, does as well. Thus, these findings reveal that the Crabtree effect strongly depends on the ratio between these two glycolysis-derived hexose phosphates. Last, in silico modeling of the Crabtree effect illustrated the requirement of an inhibition of the respiratory flux by a coordinated variation of glucose-6-phosphate and fructose-1,6-bisphosphate to fit the respiratory rate decrease observed upon glucose addition to cells. In summary, we conclude that two glycolysis-derived hexose phosphates, G6P and F1,6bP, play a key role in the induction of the Crabtree effect.

Highlights

The Crabtree effect was first described by H
The Crabtree effect is due to an inhibition of the mitochondrial respiratory chain We investigated the induction of the Crabtree effect in our model S. cerevisiae
To determine whether this inhibition was due to a respiratory chain inhibition or to a decrease in the phosphorylation processes at the mitochondrial level, we assessed the respiratory rate under uncoupled conditions, where the respiratory chain flux is at a maximal rate

Summary

Results

The Crabtree effect is due to an inhibition of the mitochondrial respiratory chain We investigated the induction of the Crabtree effect in our model S. cerevisiae. As previously shown [12], glucose addition to yeast cells grown on non-fermentative substrate induced a decrease in respiratory rate (Fig. 1A). To determine whether this inhibition was due to a respiratory chain inhibition or to a decrease in the phosphorylation processes at the mitochondrial level, we assessed the respiratory rate under uncoupled conditions, where the respiratory chain flux is at a maximal rate.

The abbreviations used are

Discussion

Experimental procedures