IMPACT

Involvement of Mitochondrial PyruvAte Carrier in Tumorogenesis

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Recent studies highlighted the role of metabolism in a number of human malignancies. Pyruvate is the key player in cellular metabolism in mitochondria and its regulation might be altered in cancer cells.

Descrizione progetto (Article)

Cancer cells can modify their metabolism to proliferate and to adapt to stressful environmental conditions. In many cases, cancer cells adapt to adenosine triphosphate (ATP) production through glycolysis versus its generation through oxidative phosphorylation. This shift is known as the Warburg effect.

Pyruvate is an important metabolite that plays a role in switching between glycolysis in the cytosol and oxidative phosphorylation in mitochondria. The objectives of the EU-funded 'Involvement of mitochondrial pyruvate carrier in tumorogenesis' (IMPACT) project have been to investigate the functional properties of the mitochondrial pyruvate carrier (MPC) in normal and cancer cells.

MPC imports pyruvate inside mitochondrion if it is not reduced into lactate by lactate dehydrogenase. Researchers hypothesised that abnormal activity of the MPC in cancer cells causes, at least in part, the Warburg effect.

Researchers genetically engineered a biosensor that was based on bioluminescence resonance energy transfer (BRET) to monitor activity of the MPC. After obtaining proof-of-concept for the biosensor, they determined MPC activity in a number of normal and cancer cells. The generated cell lines stably expressed the MPC BRET sensor. These experiments allowed validating the functionality of the BRET sensor.

IMPACT members observed an increase in MPC activity in both normal and cancer cells in response to pyruvate. These types of changes were not observed in cancer cells when glucose was provided as the only carbon source. The results suggest that changes in pathways upstream of pyruvate import mostly resulted in the Warburg effect observed in different tumours.

The novel BRET assay allows identification of the mechanisms that prevent pyruvate from being imported into mitochondria. Proteins involved in this process might present new therapeutic targets for cancer treatment.