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Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP). UCPs separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as the mitochondrial proton leak. UCPs facilitate the transfer of anions from the inner to the outer mitochondrial membrane and the return transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. Tissue specificity occurs for the different UCPs and the exact methods of how UCPs transfer H+/OH- are not known. UCPs contain the three homologous protein domains of MACPs. This gene has tissue-specific transcription initiation with other transcription initiation sites upstream of SM-1 (major skeletal muscle site). Chromosomal order is 5'-UCP3-UCP2-3'. Two splice variants have been found for this gene. Association between BMI and the UCP3 -55 C-->T polymorphism in diabetic nephropathy. Decreased mitochondrial proton leak and reduced expression in skeletal muscle of obese diet-resistant women. Depressed UCP3 expression may be an important mechanism for reducing the formation of oxygen-derived free radicals. Fasting activates the gene expression of UCP3 independent of lipid transport and oxidation genes in skeletal muscle suggesting a role in regulation of FA homeostasis during fasting. IGF-1 may protect from hyperglycemia-induced oxidative stress and neuronal injuries by regulating mitochondrial membrane potential, possibly by the involvement of UCP3. Metabolic and anthropometric factors related to skeletal muscle UCP3 gene expression in healthy human adults. No association was found between the -55 C/T polymorphism within the uncoupling protein 3 gene and the ultra-endurance performance of triathletes. Our results suggest that the LEP and UCP2/UCP3 genes are unlikely to have a substantial effect on variation in obesity phenotypes in this particular US Caucasian population. Results support a role for UCP3 in fuel substrate management and energy metabolism, which may influence body weight regulation. The hypothesis that differences in the UCP-3 genes influence the susceptibility to anorexia nervossa was not supported. This is the first study to demonstrate a downregulation of skeletal muscle UCP3 mRNA expression after the lowering of plasma free fatty acids concentrations in humans, despite an increase in energy expenditure upon beta2-adrenergic stimulation. Training status did not change skeletal muscle fiber hierarchical UCP3 protein expression in different fiber types. It affected UCP3 content more in type I and type IIa than in type IIx muscle fibers. UCP3 gene transcription is activated by thyroid hormone treatment in vivo, and this activation is mediated by a TRE (thyroid hormone response element) in the proximal promoter region. UCP3 protein content is related to energy metabolism in humans and might help in the metabolic adaptation to cold exposure. UCPs in adipose tissue may play a role in the reduction in 24-h energy expenditure observed in post-obese individuals. Uncoupling protein 3 gene is associated with body composition changes with training. Uncoupling protein 3 polymorphisms are associated with waist-to-hip ratio. Up-regulation of UCP3 in riboflavin-responsive, multiple acylcoenzyme A dehydrogenase deficiency is due to accumulation of muscle fatty acid/acylCoA. Convergence of MyoD and PPAR-dependent pathways provides a molecular mechanism for skeletal muscle specificity and fatty acid regulation of the human UCP3 gene. Expression of UCP3 mRNA was dependent on human muscle differentiation. Microsatellite markers at the UCP2/UCP3 locus on chromosome 11q13 in anorexia nervosa. Mitochondrial uncoupling protein, involved in thermogenesis. mRNA levels elevated in weight loss associated with gastrointestinal adenocarcioma. Purine nucleotides must be the physiological inhibitors of UCP3-mediated uncoupling in vivo. Review. Role of UCP3 in postnatal activation of lipid oxidation in skeletal muscle and suggest the involvement of UCP3 in the delayed activation of mitochondrial energy conversion in very immature preterm neonates. Study of isolation, refolding, transport properties, and regulation of recombinant UCP3.
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