A. Negresalvayre et al., ROLE FOR UNCOUPLING PROTEIN-2 AS A REGULATOR OF MITOCHONDRIAL HYDROGEN-PEROXIDE GENERATION, The FASEB journal, 11(10), 1997, pp. 809-815
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.