Mitochondrial proton leaks and uncoupling proteins

• Published in: Biochimica et biophysica acta. Bioenergetics 2021-07, Vol.1862 (7), p.148428-148428, Article 148428
• Main Author: Nicholls, David G.
• Format: Article
• Language: English
• Subjects: Brown adipose tissue; Brown fat; Mitochondria; UCP1; UCP2; UCP3; Uncoupling protein
• ISSN: 0005-2728; 1879-2650
• DOI: 10.1016/j.bbabio.2021.148428

Non-shivering thermogenesis in brown adipose tissue is mediated by uncoupling protein 1 (UCP1), which provides a carefully regulated proton re-entry pathway across the mitochondrial inner membrane operating in parallel to the ATP synthase and allowing respiration, and hence thermogenesis, to be released from the constraints of respiratory control. In the 40 years since UCP1 was first described, an extensive, and frequently contradictory, literature has accumulated, focused on the acute physiological regulation of the protein by fatty acids, purine nucleotides and possible additional factors. The purpose of this review is to examine, in detail, the experimental evidence underlying these proposed mechanisms. Emphasis will be placed on the methodologies employed and their relation to the physiological constraints under which the protein functions in the intact cell. The nature of the endogenous, UCP1-independent, proton leak will also be discussed. Finally, the troubled history of the putative novel uncoupling proteins, UCP2 and UCP3, will be evaluated. •The experimental evidence supporting models of the acute regulation of uncoupling protein 1 is examined.•The importance of physiologically relevant constraints is emphasized.•Were SLC25A8 (UCP2) and SLC25A9 (UCP3) correctly designated as uncoupling proteins?