Retinoids activate proton transport by the uncoupling proteins UCP1 and UCP2.
In mammalian brown adipose tissue, thermogenesis is explained by uncoupling mitochondrial respiration from ATP synthesis. Uncoupling protein-1 (UCP1) is responsible for this uncoupled state, because it allows proton re-entry into the matrix and thus dissipates the proton gradient generated by the respiratory chain. Proton transport by UCP1 is regulated negatively by nucleotides and positively by fatty acids. Adrenergic stimulation of brown adipocytes stimulates lipolysis and therefore enhances uncoupling and thermogenesis. Adrenergic stimulation also boosts ucp1 gene transcription. Since retinoic acid also promotes ucp1 gene transcription and its structure makes it a possible activator of UCP1, we hypothesized that retinoic acid, like noradrenaline, could have a dual action and trigger the activity of the protein UCP1 itself. Here we show that retinoic acid strongly increases proton transport by UCP1 in brown adipose tissue mitochondria and that it is much more potent than fatty acids. These data are corroborated with yeast mitochondria where UCP1 was introduced by genetic manipulation. The yeast expression system allows the comparison of the UCP1 with the newly described homologues UCP2 and UCP3. The search for regulators of UCP2 has demonstrated that it is positively regulated by retinoids in a pH-dependent manner.
Rial
E
E
Centro Investigaciones Biologicas, CSIC, Velazquez 144, 28006 Madrid, Spain.
González-Barroso
M
M
Fleury
C
C
Iturrizaga
S
S
Sanchis
D
D
Jiménez-Jiménez
J
J
Ricquier
D
D
Goubern
M
M
Bouillaud
F
F
D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D015394:Molecular Structure; D010101:Oxygen Consumption / Q000187:drug effects; D019308:Palmitic Acid / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D011522:Protons; D051381:Rats; D012176:Retinoids / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2
D001565:Benzoates; D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D011522:Protons; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C000604372:Ucp1 protein, mouse; C000604373:Ucp1 protein, rat; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; C068073:Am 580; D019308:Palmitic Acid; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid