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

Cavalieri, Riccardo, Dela Rosa, Margeoux A. S., Cotrim, Camila A., Copeman, Danielle, Aris, Mehmethan, Eke, Callum, Staggs‐Sandy, Hannah and Crichton, Paul G. (2026) A Structural Context for the Mechanisms of Uncoupling Protein 1 in Brown Fat Thermogenesis. Acta Physiologica, 242 (6). ISSN 1748-1708 (In Press)

Preview

PDF (Acta Physiologica - 2026 - Cavalieri - A Structural Context for the Mechanisms of Uncoupling Protein 1 in Brown Fat) - Published Version Available under License Creative Commons Attribution. Download (2MB) | Preview

Abstract

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 pro-duction 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 con-text. 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.

Item Type:	Article
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Groups > Cardiovascular and Metabolic Health
Related URLs:	https://onlinelibrary.wiley.com/doi/10.1...
Depositing User:	LivePure Connector
Date Deposited:	14 May 2026 15:53
Last Modified:	14 May 2026 15:53
URI:	https://ueaeprints.uea.ac.uk/id/eprint/103040
DOI:	10.1111/apha.70246

Downloads

Actions (login required)

View Item