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Étude de l’effet Warburg, à l’origine du métabolisme énergétique de la cellule cancéreuse, chez la levure Saccharomyces cerevisiae

Abstract : We used the yeast Crabtree (+) model to study the relationships between the energy metabolism pathways during the implementation of the Warburg effect. The effect of glucose on S. cerevisiae energetic metabolism results initially in a kinetic inhibition of the oxidative metabolism (Crabtree effect). Rapidly after the addition of glucose, we found an accumulation of F1, 6bP. This induces a drastic reduction in the ratio G6P / F1,6bP. Moreover, it has been shown that G6P stimulates and F1,6bP inhibits the activity of the respiratory chain "in-vitro". Mutants and the modulation of this ratio allowed us to show that the induction of the Crabtree effect is due to a decrease in the G6P / F1,6bP ratio. In parallel with the implementation of the Crabtree effect, glucose induces a genetic rearrangement that leads to a Warburg effect. We showed a decrease over time of mitochondrial enzymatic equipment by dilution effect, due to a halt of mitochondrial biogenesis (transcriptional repression of HAP4). We have been able to show that this decrease in respiratory capacity has no effect on the cellular capacity for ATP synthesis. This is due to the increase in glycolytic ATP synthesis flux. Furthermore, the use of mutants where there is no repression of mitochondrial metabolism upon glucose addition allowed us to show that there is no simple link between OXPHOS activity and cell proliferation. i.e. Mitochondrial metabolism repression/high glycolytic flux is not mandatory to allow a rapid cell proliferation. This is a rare example where energetic metabolism and cell proliferation are uncoupled.
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Noureddine Hammad. Étude de l’effet Warburg, à l’origine du métabolisme énergétique de la cellule cancéreuse, chez la levure Saccharomyces cerevisiae. Médecine humaine et pathologie. Université de Bordeaux, 2018. Français. ⟨NNT : 2018BORD0180⟩. ⟨tel-02091494⟩

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