title: UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation.
abstract: 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.
authors.affiliation: Department of Biosciences, Biotechnologies, and Biopharmaceutics and Center of Excellence in Comparative Genomics, University of Bari, 70125 Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Vozza
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parisi
authors.forename: Francesco
authors.initials: F
authors.lastname: De Leonardis
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Lasorsa
authors.forename: Alessandra
authors.initials: A
authors.lastname: Castegna
authors.forename: Daniela
authors.initials: D
authors.lastname: Amorese
authors.forename: Raffaele
authors.initials: R
authors.lastname: Marmo
authors.forename: Valeria M
authors.initials: VM
authors.lastname: Calcagnile
authors.forename: Luigi
authors.initials: L
authors.lastname: Palmieri
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricquier
authors.forename: Eleonora
authors.initials: E
authors.lastname: Paradies
authors.forename: Pasquale
authors.initials: P
authors.lastname: Scarcia
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Palmieri
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bouillaud
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fiermonte
mesh_terms: D002244:Carbon / Q000737:chemistry*; D002384:Catalysis; D019069:Cell Respiration / Q000502:physiology; D002952:Citric Acid Cycle; D004734:Energy Metabolism; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D008081:Liposomes / Q000737:chemistry; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D062907:Oxaloacetic Acid / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry*; D010101:Oxygen Consumption; D010710:Phosphates / Q000737:chemistry; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D008081:Liposomes; D024101:Mitochondrial Proteins; D010710:Phosphates; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D005973:Glutamine; D062907:Oxaloacetic Acid; D002244:Carbon; D005947:Glucose; D010100:Oxygen
keywords: Warburg effect; diabetes; glucose and glutamine metabolism; metabolic reprogramming; mitochondrial carrier