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Involvement of Mitochondrial PyruvAte Carrier in Tumorogenesis (IMPACT)
Date du début: 1 juin 2013, Date de fin: 31 mai 2015 PROJET  TERMINÉ 

"The role of metabolism in cancer has attracted massive attention in recent years. Several studies highlighted the relevance of aberrant metabolic activities in a number of malignancies. A key node of eukaryotic metabolism is the transport of pyruvate between cytoplasm and mitochondria. Pyruvate, the end product of glycolysis, plays an essential role in cellular metabolism as after transport into mitochondria it can be oxidized into acetyl-CoA, and further oxidized in the tricarboxylic acid cycle. The transport of pyruvate into mitochondria is therefore essential for oxidative phosphorylation and may, under some circumstances, represent a rate-limiting step for oxidative phosphorylation. A few months ago, a major step was achieved with the molecular identification of the mitochondrial pyruvate carrier by the group of Dr Martinou, the host laboratory.In a number of cancers, cytosolic pyruvate is converted to lactate, a phenomenon known as the Warburg effect. The mechanisms underlying the Warburg effect have not been completely elucidated. We hypothesize that the structure and/or function of the mitochondrial pyruvate carrier is altered in a number of cancers, resulting in significant metabolic changes that could, at least in part, explain the Warburg effect.The aims of this proposal are to characterize the structural and functional properties of the mitochondrial pyruvate carrier and to assess how they may impact on mitochondrial pyruvate import and cell metabolism in cancer cells. Moreover, using a genetic approach in yeast, we will search for genes that allow cancer cells to survive and proliferate normally with decreased activity of the mitochondrial pyruvate carrier.My work should provide key information on the regulation of this newly discovered mitochondrial pyruvate transporter in cancer metabolism and may lead to the identification of therapeutic targets for cancer."