ROLE FOR UNCOUPLING PROTEIN-2 AS A REGULATOR OF MITOCHONDRIAL HYDROGEN-PEROXIDE GENERATION

According to the state of mitochondrial respiration, the respiratory c hain generates superoxide anions converted into hydrogen peroxide. Two uncoupling proteins (UCP) able to modulate the coupling between the r espiratory chain and ATP synthesis are now identified and could be inv olved in mitochondrial H2O2 generation. UCP1 is specific to brown adip ose tissue (BAT) whereas UCP2 is expressed in numerous tissues, partic ularly in monocytes/macrophages. Preincubation of BAT mitochondrial fr actions with GDP, an inhibitor of UCP1, induced a rise in mitochondria l membrane potential (assessed by rhodamine 123 uptake) and H2O2 produ ction. An uncoupling agent reversed this effect. Liver mitochondria ex hibited a similar phenotype. CDP was also able to raise membrane poten tial and H2O2 production of the mitochondria from nonparenchymal cells expressing UCP2, but was completely ineffective on mitochondria from hepatocytes deprived of UCP2. The GDP effect was also observed with mi tochondrial fractions of the spleen or thymus, which highly expressed UCP2. Altogether, these results strongly suggest that UCP2 is sensitiv e to GDP and that the UCPs, particularly UCP2, are able to modulate H2 O2 mitochondrial generation. This supports a role for UCP2 in cellular (patho-) physiological processes involving free radicals generated by mitochondria, such as oxidative damage, inflammation, or apoptosis.