Structural models of mitochondrial uncoupling proteins obtained in DPC micelles are not functionally relevant

FEBS J. 2021 May;288(9):3024-3033. doi: 10.1111/febs.15629. Epub 2020 Dec 7.


Uncoupling protein 1 (UCP1) is found in the inner mitochondrial membrane of brown adipocytes. In the presence of long-chain fatty acids (LCFAs), UCP1 increases the proton conductance, which, in turn, increases fatty acid oxidation and energy release as heat. Atomic models of UCP1 and UCP2 have been generated based on the NMR backbone structure of UCP2 in dodecylphosphocholine (DPC), a detergent known to inactivate UCP1. Based on NMR titration experiments on UCP1 with LCFA, it has been proposed that K56 and K269 are crucial for LCFA binding and UCP1 activation. Given the numerous controversies on the use of DPC for structure-function analyses of membrane proteins, we revisited those UCP1 mutants in a more physiological context by expressing them in the mitochondria of Saccharomyces cerevisiae. Mitochondrial respiration, assayed on permeabilized spheroplasts, enables the determination of UCP1 activation and inhibition. The K56S, K269S, and K56S/K269S mutants did not display any default in activation, which shows that the NMR titration experiments in DPC detergent are not relevant to UCP1 function.

Keywords: brown adipose tissue; fatty acid-binding site; mitochondria; uncoupling protein 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Brown / metabolism
  • Adipocytes, Brown / ultrastructure*
  • Animals
  • Fatty Acids / genetics
  • Fatty Acids / metabolism
  • Humans
  • Ion Channels / genetics
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Membranes / ultrastructure
  • Mitochondrial Uncoupling Proteins / chemistry
  • Mitochondrial Uncoupling Proteins / ultrastructure*
  • Models, Structural
  • Oxygen Consumption / genetics
  • Phosphorylcholine / analogs & derivatives
  • Phosphorylcholine / chemistry
  • Protein Conformation*
  • Protons
  • Rats
  • Saccharomyces cerevisiae
  • Structure-Activity Relationship
  • Uncoupling Protein 1 / chemistry
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / ultrastructure*


  • Fatty Acids
  • Ion Channels
  • Mitochondrial Uncoupling Proteins
  • Protons
  • Ucp1 protein, rat
  • Uncoupling Protein 1
  • Phosphorylcholine
  • dodecylphosphocholine