Uncoupling protein 2 (UCP2) is involved in various physiological and
pathological processes such as insulin secretion, stem cell differentiation,
cancer, and aging. However, its biochemical and physiological function is still under debate. Here we show that UCP2 is a metabolite transporter that regulates substrate oxidation in mitochondria. To shed light on its biochemical role, we first studied the effects of its silencing on the mitochondrial oxidation of
glucose and
glutamine. Compared with wild-type, UCP2-silenced human
hepatocellular carcinoma (HepG2) cells, grown in the presence of
glucose, showed a higher inner mitochondrial membrane potential and
ATP:
ADP ratio associated with a lower
lactate release. Opposite results were obtained in the presence of
glutamine instead of
glucose. UCP2 reconstituted in
lipid vesicles catalyzed the exchange of
malate,
oxaloacetate, and
aspartate for
phosphate plus a
proton from opposite sides of the membrane. The higher levels of citric acid cycle intermediates found in the mitochondria of siUCP2-HepG2 cells compared with those found in wild-type cells in addition to the transport data indicate that, by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of
acetyl-CoA-producing substrates such as
glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from
glutamine. Our work reveals a unique regulatory mechanism in cell bioenergetics and provokes a substantial reconsideration of the physiological and pathological functions ascribed to UCP2 based on its purported uncoupling properties.