A Structural Context for the Mechanisms of Uncoupling Protein 1 in Brown Fat Thermogenesis

Uncoupling Protein 1 (UCP1) is a defining feature of brown fat and facilitates the specialized ability of the tissue to generate heat in the process of non-shivering thermogenesis. The protein is activated by fatty acids, which overcome its inhibition by purine nucleotides, to catalyze proton leak across the mitochondrial inner membrane, uncoupling nutrient oxidation from ATP production to release energy as heat. Thermogenesis through this process contributes to thermoregulation in many mammals and can promote nutrient turnover in humans to support metabolic health. UCP1 is a member of the mitochondrial carrier family of solute exchangers. For many years, its underlying mechanisms of activity and regulation have remained unclear. However, recent cryo-EM structures of UCP1 have clarified details on nucleotide inhibition and, with advances in our understanding of the mitochondrial carrier transport mechanism, provided important molecular constraints to rationalize how the protein may operate. Here, we review the molecular nature of UCP1, re-evaluating past structure-function relations in this structural context. Key carrier features and putative novel bonding that likely support state changes in the protein and proton leak activity are highlighted, as well as new hypotheses to explain subtleties in purine nucleotide binding discrimination.