Activation by retinoids of the uncoupling protein UCP1

Biochim Biophys Acta. 2004 Jul 23;1658(1-2):157-64. doi: 10.1016/j.bbabio.2004.05.010.


The uncoupling protein from brown adipose tissue (UCP1) is a transporter that catalyzes a regulated discharged of the mitochondrial proton gradient. The proton conductance in UCP1 is inhibited by nucleotides and activated by fatty acids. We have recently shown that all-trans-retinoic acid (ATRA) is a high-affinity activator of UCP1. In the present report, we have set to analyze the structural requirements for the ligands that activate UCP1 and particularly the specificity for different retinoids. For this purpose, we have developed a new protocol to determine the activity of UCP1 in respiring yeast mitochondria that can be adapted for high-throughput screenings. Our results evidence differences between the structural requirements for the activation by fatty acids and retinoids. Thus, although all active retinoids must possess a carboxylate, the introduction of additional polar groups renders them inactive. The linear and rigid structure of these molecules suggests the existence of a long hydrophobic binding pocket. We postulate that the access to the retinoid binding site must occur from the lipid bilayer and this could be at the interface between two transmembrane alpha-helices.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / agonists
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Fatty Acids / chemistry
  • Fatty Acids / pharmacology
  • Ion Channels
  • Membrane Proteins / agonists
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondrial Proteins
  • Molecular Structure
  • NAD / metabolism
  • Oxygen Consumption
  • Recombinant Proteins / metabolism
  • Retinoids / chemistry
  • Retinoids / pharmacology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Uncoupling Protein 1


  • Carrier Proteins
  • Fatty Acids
  • Ion Channels
  • Membrane Proteins
  • Mitochondrial Proteins
  • Recombinant Proteins
  • Retinoids
  • Uncoupling Protein 1
  • NAD