UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation
| Autor: | Pasquale Scarcia, Ferdinando Palmieri, Valeria Mariajolanda Calcagnile, Giuseppe Fiermonte, Luigi Palmieri, Francesco De Leonardis, Daniela Amorese, Daniel Ricquier, Alessandra Castegna, Giovanni Parisi, Eleonora Paradies, Raffaele Marmo, Frédéric Bouillaud, Francesco M. Lasorsa, Angelo Vozza |
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| Rok vydání: | 2014 |
| Předmět: |
Oxaloacetic Acid
Cellular respiration Glutamine Cell Respiration Citric Acid Cycle Mitochondrion Catalysis Ion Channels Phosphates Mitochondrial Proteins Oxygen Consumption Humans Citrate synthase Uncoupling Protein 2 Gene Silencing Inner mitochondrial membrane Membrane Potential Mitochondrial Multidisciplinary Glutaminolysis biology Hep G2 Cells Biological Sciences Mitochondrial carrier Carbon Mitochondria Cell biology Oxygen Citric acid cycle Glucose HEK293 Cells Biochemistry Liposomes biology.protein Energy Metabolism |
| Zdroj: | Proceedings of the National Academy of Sciences. 111:960-965 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1317400111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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