Presentation description

The mitochondrial pyruvate carrier (MPC) is a transmembrane protein in the inner mitochondria membrane and facilitates the entry of pyruvate, which is a major fuel of the TCA cycle. Our lab has previously shown that MPC expression is negatively correlated with Wnt/beta-catenin target gene expression, and its required for invasion and proliferation of cancer cells. However, the molecular mechanism behind these effects are not known. Based on our preliminary observations, we hypothesize that beta-catenin acts as a repressor of the MPC. To test this hypothesis, we first performed a Fluorescence-activated cell sorting (FACS)-based genetic screening assay and found that beta-catenin acts as a repressor of the MPC in liver cancer cells. Using RT-qPCR and Immunoblotting, we validated this finding by showing that treatment with GSK3 inhibitors, which activate the Wnt/beta-catenin pathway, caused reduced MPC mRNA and protein expression. Moreover, we tested whether low MPC expression upon beta-catenin activation was affecting the ability of the mitochondria to use different metabolic fuels. Using a Seahorse metabolic assay, we found that activation of beta-catenin resulted in more fatty acid oxidation in liver cancer cells with low MPC expression. Overall, our results suggest that activation of beta-catenin results in decreased MPC transcripts/protein levels, and rewires its metabolism. Taken together, we proposed a model where beta-catenin acts as a repressor of the MPC in liver cancer cells. Future studies will be focused on characterizing the mechanisms by which MPC expression is regulated by the Wnt/beta-catenin pathway and the significance of this regulation in cell fate.