Abstract

In numerous cell types, tumoral cells, proliferating cells, bacteria, and yeast, respiration is inhibited when high concentrations of glucose are added to the culture medium. This phenomenon has been named the "Crabtree effect." We used yeast to investigate (i) the short term event(s) associated with the Crabtree effect and (ii) a putative role of hexose phosphates in the inhibition of respiration. Indeed, yeast divide into "Crabtree-positive," where the Crabtree effect occurs, and "Crabtree-negative," where it does not. In mitochondria isolated from these two categories of yeast, we found that low, physiological concentrations of glucose 6-phosphate and fructose 6-phosphate slightly (20%) stimulated the respiratory flux and that this effect was strongly antagonized by fructose 1,6-bisphosphate (F16bP). On the other hand, F16bP by itself was able to inhibit mitochondrial respiration only in mitochondria isolated from a Crabtree-positive strain. Using permeabilized spheroplasts from Crabtree-positive yeast, we have shown that the sole effect observed at physiological concentrations of hexose phosphates is an inhibition of oxidative phosphorylation by F16bP. This F16bP-mediated inhibition was also observed in isolated rat liver mitochondria, extending this process to mammalian cells. From these results and taking into account that F16bP is able to accumulate in the cell cytoplasm, we propose that F16bP regulates oxidative phosphorylation and thus participates in the establishment of the Crabtree effect.

Highlights

  • In aerobic organisms, glycolysis and oxidative phosphorylation are coordinated to fulfill the cell energy demand

  • From results obtained with reconstituted systems [12] and with mitochondria isolated from potato tubers [13], it was suggested that cytosolic NADH produced by glycolysis could close the voltage-dependent anionic channel and limit the passage of molecules such as ADP toward the intermembrane space

  • In order to study such a process, we took advantage of the existence of Crabtree-positive (S. cerevisiae) and Crabtree-negative (C. utilis) yeast strains. In both kinds of isolated mitochondria, we found that low, physiological concentrations of glucose 6-phosphate (G6P) and fructose 6-phosphate (F6P) stimulated the respiratory flux (JO2), and this effect was strongly antagonized by fructose 1,6-bisphosphate (F16bP)

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Summary

A POSSIBLE ROLE IN CRABTREE EFFECT INDUCTION?*

Using permeabilized spheroplasts from Crabtree-positive yeast, we have shown that the sole effect observed at physiological concentrations of hexose phosphates is an inhibition of oxidative phosphorylation by F16bP This F16bP-mediated inhibition was observed in isolated rat liver mitochondria, extending this process to mammalian cells. A yeast mutant that lacks trehalose 6-phosphate synthase (Tps1p) overaccumulates glycolysis hexose phosphates in response to glucose [24] It has not been clearly demonstrated whether metabolic intermediates could function as messengers in long or short term regulatory events. In order to study such a process, we took advantage of the existence of Crabtree-positive (S. cerevisiae) and Crabtree-negative (C. utilis) yeast strains In both kinds of isolated mitochondria, we found that low, physiological concentrations of G6P and fructose 6-phosphate (F6P) stimulated the respiratory flux (JO2), and this effect was strongly antagonized by fructose 1,6-bisphosphate (F16bP).

The abbreviations used are
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
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