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

Abstract

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
DOIs
Publication statusE-pub ahead of print - 1 Apr 2024

Keywords

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

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