Retinoids activate proton transport by the uncoupling proteins UCP1 and UCP2

Abstract

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.

The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP

“…Using the same experimental conditions, these regulators did not affect UCP3 activity expressed in yeast [115]. Taken together, all these data suggest that the regulation of UCP1, UCP2 and UCP3 activity by ligands may somehow differ.…”

“…Retinoids were identified as novel regulators of the uncoupling activity of UCP1 and UCP2 when tested in yeast mitochondria [115]. Using the same experimental conditions, these regulators did not affect UCP3 activity expressed in yeast [115].…”

“…Since these tissues contain no UCP1, but express the UCP2 gene, the authors concluded that UCP2 is a regulator of mitochondrial H # O # production [124]. Although such a role for UCP2 may exist, the conclusion of the authors remains questionable, since the inhibition of UCP2 activity by GDP was not demonstrated and since no inhibition or a partial inhibition of UCP2 by nucleotides has been observed by others [112,115].…”

“…However, using yeast mitochondria containing UCP2 or UCP3, we were unable to measure any activation of the proteins by fatty acids, under conditions where a net activation of UCP1 was recorded [115]. We and others were also unable to inhibit the uncoupling activity of UCP2 and UCP3 by adding nucleotides to isolated mitochondria [111,115]. Interestingly, using liposomes, Jaburek et al [112] observed that the proton transport activity of UCP2 and UCP3 was not inhibited by low concentrations of nucleotides, with such an inhibition being observed only with high levels of nucleotides.…”

Association of UCP2 −866 G/A polymorphism with chronic inflammatory diseases

“…4,7,8 High expression of UCP2 has been reported in cells of the immune system, and the expression was affected by the -866 G variation in vivo and in vitro. 4,9,10 The -866 G allele decreasing the UCP2 expression is associated with increased risk to chronic inflammatory diseases. This observation is consistent with findings in mouse studies, where UCP2-deficient mice were more susceptible to experimental autoimmune encephalomyelitis (EAE) and showed stronger immune responses to infections than wild-type controls.…”