UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation

Significance Mitochondrial carriers constitute a large family of transport proteins that play important roles in the intracellular translocation of metabolites, nucleotides, and coenzymes. Despite considerable research efforts, the biochemical function of Uncoupling protein 2 (UCP2), a member of the mitochondrial carrier family reported to be involved in numerous pathologies, is still elusive. Here we show that UCP2 catalyzes an exchange of malate, oxaloacetate, and aspartate for phosphate, and that it exports C4 metabolites from mitochondria to the cytosol in vivo. Our findings also provide evidence that UCP2 activity limits mitochondrial oxidation of glucose and enhances glutaminolysis. These results provide a unique regulatory mechanism in cell bioenergetics and explain the significance of UCP2 levels in metabolic reprogramming occurring under various physiopathological conditions.