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    • G007-LK It remains unclear to what extent UCP and UCP are

    2022-12-02

    It remains unclear to what extent UCP2 and UCP3 are subject to the same acute molecular regulation as UCP1 (and the extent to which they share the same mechanism of uncoupling). Although they lack sequence homology in a matrix-localised region reportedly critical for fatty G007-LK activation of UCP1 [17], proteoliposome studies show that UCP2 and UCP3 have similar fatty acid-activated proton conductance and purine nucleotide inhibition as UCP1 [18], [19], [20]. One difficulty has been the inability to directly compare UCPs in mitochondria, since UCP2 and UCP3 are expressed in different tissues and at hundred-fold lesser amounts than UCP1 [21], [22], [23]. Another difficulty relates to the fact that GDP has been shown to inhibit uncoupling via ANT [24], [25] as well as by the UCPs. This complicates the calculations of UCP-mediated proton leak in tissues that express different amounts of UCP and ANT when activity is defined as GDP-sensitive uncoupling. There is evidence that superoxide, both exogenous [26] and endogenous [27], and lipid peroxidation products such as hydroxynonenal [25], [28], [29] can activate uncoupling by all three UCPs, suggesting a model in which superoxide reacts with membrane phospholipids to generate the proximal activator, hydroxynonenal [28], [30]. The physiological relevance of this model, which has not been reproduced in all laboratories, remains controversial [10], [31], [32], [33].
    Role and regulation of uncoupling proteins The archetypal uncoupling protein, UCP1, is best known for its role in adaptive non-shivering thermogenesis and control of body weight, whereby a cold stimulus or over-feeding results in sympathomimetic stimulation of β3-adrenergic receptors in BAT. This leads to upregulation of Ucp1 mRNA expression via a BAT-specific enhancer box [34], activation of UCP1 by fatty acids [35] produced from lipolysis [36], and the transduction of the mitochondrial protonmotive force into heat [37]. Indeed Ucp1 knockout results in the absence of non-shivering thermogenesis [38], loss of cold tolerance [39] and appearance of obesity at thermoneutrality [40]. Beyond thermogenesis, the role of UCP1 in thymus [41], [42] and in ectotherms [43] remains speculative. The UCP1 paralogues, UCP2 and UCP3, probably evolved from a duplication event in vertebrates. This is supported by their juxtaposition in the genome and their high sequence identity with each other (72–74% from fish to mammals). Sequence analysis shows that unlike UCP1, UCP2 and UCP3 are under strong purifying selection, suggesting that they have not changed function during evolution [44]. The literature varies on whether or not UCP2 and UCP3 are upregulated in response to cold in various organisms and tissues [45], [46], [47], but they are not thought to be significantly thermogenic [48], primarily because of their low abundance. However, rodent UCP3 can participate in thermogenesis under particular conditions [49], [50]. UCP2 and UCP3 are also upregulated in response to starvation, and have been linked with a number of processes including insulin secretion from pancreatic β-cells [51] and insulin resistance [52] in peripheral tissues, as well as modulation of reactive oxygen species production and immune responses [10], [53], [54], [55].
    Turnover of uncoupling proteins UCP1 half-life in BAT is in the order of hours to days and is significantly increased by administration of noradrenaline, which also upregulates UCP1 synthesis [112]. However, the mechanism of turnover remained uncertain until Desautels and colleagues showed that the proteolytic rates of other mitochondrial proteins parallel those for UCP1, and that the half-lives of UCP1 and other mitochondrial proteins are delayed by lysosomal inhibition [113], [114]. The half-life and turnover mechanism of UCP1 differs from that of its homologues UCP2 and UCP3. These both have unusually short half-lives, which are at least an order of magnitude lower than that for UCP1. UCP2 has a half-life of one hour in a range of tissues [83], [115], including pancreatic β-cell models [87]. We showed that this rapid half-life is not a general feature of mitochondrial inner membrane proteins like ANT, and is not recapitulated in isolated energised mitochondria, suggesting that an extramitochondrial factor may be required for efficient UCP2 degradation [87]. We further demonstrated that this extramitochondrial factor is the cytosolic proteasomal machinery [116]. Use of proteasome inhibitors, ubiquitin mutants and a novel cell-free reconstituted system showed that cytosolic proteasomal function is required for rapid UCP2 degradation in cells and in isolated mitochondria [116]. How this cytosolic machinery accesses inner membrane residing UCP2 despite the interposition of the mitochondrial outer membrane remains unknown, but our working models of how this might be achieved are shown in Fig. 2.