Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria

Cell. 2012 Oct 12;151(2):400-13. doi: 10.1016/j.cell.2012.09.010.


Mitochondrial uncoupling protein 1 (UCP1) is responsible for nonshivering thermogenesis in brown adipose tissue (BAT). Upon activation by long-chain fatty acids (LCFAs), UCP1 increases the conductance of the inner mitochondrial membrane (IMM) to make BAT mitochondria generate heat rather than ATP. Despite being a member of the family of mitochondrial anion carriers (SLC25), UCP1 is believed to transport H(+) by an unusual mechanism that has long remained unresolved. Here, we achieved direct patch-clamp measurements of UCP1 currents from the IMM of BAT mitochondria. We show that UCP1 is an LCFA anion/H(+) symporter. However, the LCFA anions cannot dissociate from UCP1 due to hydrophobic interactions established by their hydrophobic tails, and UCP1 effectively operates as an H(+) carrier activated by LCFA. A similar LCFA-dependent mechanism of transmembrane H(+) transport may be employed by other SLC25 members and be responsible for mitochondrial uncoupling and regulation of metabolic efficiency in various tissues.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Binding Sites
  • Cytoplasm / metabolism
  • Fatty Acids / metabolism*
  • Ion Channels / antagonists & inhibitors
  • Ion Channels / metabolism*
  • Mice
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / antagonists & inhibitors
  • Mitochondrial Proteins / metabolism*
  • Patch-Clamp Techniques
  • Protons
  • Purines / metabolism
  • Uncoupling Protein 1


  • Fatty Acids
  • Ion Channels
  • Mitochondrial Proteins
  • Protons
  • Purines
  • Ucp1 protein, mouse
  • Uncoupling Protein 1