Superoxide activates mitochondrial uncoupling proteins.
Uncoupling protein 1 (UCP1) diverts energy from ATP synthesis to thermogenesis in the mitochondria of brown adipose tissue by catalysing a regulated leak of protons across the inner membrane. The functions of its homologues, UCP2 and UCP3, in other tissues are debated. UCP2 and UCP3 are present at much lower abundance than UCP1, and the uncoupling with which they are associated is not significantly thermogenic. Mild uncoupling would, however, decrease the mitochondrial production of reactive oxygen species, which are important mediators of oxidative damage. Here we show that superoxide increases mitochondrial proton conductance through effects on UCP1, UCP2 and UCP3. Superoxide-induced uncoupling requires fatty acids and is inhibited by purine nucleotides. It correlates with the tissue expression of UCPs, appears in mitochondria from yeast expressing UCP1, and is absent in skeletal muscle mitochondria from UCP3 knockout mice. Our findings indicate that the interaction of superoxide with UCPs may be a mechanism for decreasing the concentrations of reactive oxygen species inside mitochondria.
Echtay
Karim S
KS
Medical Research Council Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK.
Roussel
Damien
D
St-Pierre
Julie
J
Jekabsons
Mika B
MB
Cadenas
Susana
S
Stuart
Jeff A
JA
Harper
James A
JA
Roebuck
Stephen J
SJ
Morrison
Alastair
A
Pickering
Susan
S
Clapham
John C
JC
Brand
Martin D
MD
D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005508:Food Deprivation; D017353:Gene Deletion; D005905:Glyburide / Q000494:pharmacology; D006358:Hot Temperature; D007425:Intracellular Membranes / Q000378:metabolism; D007473:Ion Channels; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011522:Protons; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013481:Superoxides / Q000494:pharmacology*; D014475:Uncoupling Agents / Q000378:metabolism* / Q000494:pharmacology; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D011522:Protons; D017382:Reactive Oxygen Species; C000604371:UCP1 protein, human; C000604389:UCP2 protein, human; C000604392:UCP3 protein, human; C000604372:Ucp1 protein, mouse; C000604373:Ucp1 protein, rat; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; C000604393:Ucp3 protein, mouse; C000604394:Ucp3 protein, rat; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D013481:Superoxides; D005905:Glyburide