Structural mechanisms of mitochondrial uncoupling protein 1 regulation in thermogenesis

Scott A. Jones, Jonathan J. Ruprecht, Paul G. Crichton, Edmund R.S. Kunji

Research output: Contribution to journalReview articlepeer-review


In mitochondria, the oxidation of nutrients is coupled to ATP synthesis by the generation of a protonmotive force across the mitochondrial inner membrane. In mammalian brown adipose tissue (BAT), uncoupling protein 1 (UCP1, SLC25A7), a member of the SLC25 mitochondrial carrier family, dissipates the protonmotive force by facilitating the return of protons to the mitochondrial matrix. This process short-circuits the mitochondrion, generating heat for non-shivering thermogenesis. Recent cryo-electron microscopy (cryo-EM) structures of human UCP1 have provided new molecular insights into the inhibition and activation of thermogenesis. Here, we discuss these structures, describing how purine nucleotides lock UCP1 in a proton-impermeable conformation and rationalizing potential conformational changes of this carrier in response to fatty acid activators that enable proton leak for thermogenesis.

Original languageEnglish
JournalTrends in Biochemical Sciences
Publication statusE-pub ahead of print - 1 Apr 2024


  • bioenergetics
  • brown adipose tissue
  • non-shivering thermogenesis
  • SLC25 mitochondrial carrier family
  • thermogenin
  • UCP1

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