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PMID: 23063128 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cell ·Vol. 151 ·No. 2 ·2012-10-12 ·Pages 400-13

Fedorenko A, Lishko PV, Kirichok Y

Abstract

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.

MeSH Terms
Adipose Tissue, Brown/metabolism Animals Binding Sites Cytoplasm/metabolism Fatty Acids/metabolism Ion Channels/antagonists & inhibitors,metabolism Mice Mitochondrial Membranes/metabolism Mitochondrial Proteins/antagonists & inhibitors,metabolism Patch-Clamp Techniques Protons Purines/metabolism Uncoupling Protein 1
Chemicals
Fatty Acids Ion Channels Mitochondrial Proteins Protons Purines Ucp1 protein, mouse Uncoupling Protein 1
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Fedorenko Andriy
Department of Physiology, University of California San Francisco, UCSF Mail Code 2140, Genentech Hall Room N272F, 600 16th Street, San Francisco, CA 94158, USA.
Lishko Polina V
Kirichok Yuriy
References (45)
45 references, click to expand
  1. The regulation and physiology of mitochondrial proton leak.
    Physiology (Bethesda). 2011 Jun;26(3):192-205 PMID: 21670165
  2. Wanderings in bioenergetics and biomembranes.
    Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):579-94 PMID: 20175988
  3. The mechanism of proton transport mediated by mitochondrial uncoupling proteins.
    FEBS Lett. 1998 Oct 30;438(1-2):10-4 PMID: 9821950
  4. Coenzyme Q is an obligatory cofactor for uncoupling protein function.
    Nature. 2000 Nov 30;408(6812):609-13 PMID: 11117751
  5. Binding of fatty acids to the uncoupling protein from brown adipose tissue mitochondria.
    Arch Biochem Biophys. 2003 Apr 1;412(1):142-6 PMID: 12646277
  6. A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling.
    EMBO J. 2003 Aug 15;22(16):4103-10 PMID: 12912909
  7. Thermogenic mechanisms in brown fat.
    Physiol Rev. 1984 Jan;64(1):1-64 PMID: 6320232
  8. The mechanism of transport by mitochondrial carriers based on analysis of symmetry.
    Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17766-71 PMID: 19001266
  9. Membrane partition of fatty acids and inhibition of T cell function.
    Biochemistry. 1993 Jan 19;32(2):530-6 PMID: 8422363
  10. Palmitoyl coenzyme A: a possible physiological regulator of nucleotide binding to brown adipose tissue mitochondria.
    FEBS Lett. 1977 Feb 15;74(1):43-6 PMID: 838074
  11. The physiological regulation of uncoupling proteins.
    Biochim Biophys Acta. 2006 May-Jun;1757(5-6):459-66 PMID: 16725104
  12. UCP1 and defense against oxidative stress. 4-Hydroxy-2-nonenal effects on brown fat mitochondria are uncoupling protein 1-independent.
    J Biol Chem. 2006 May 19;281(20):13882-93 PMID: 16543238
  13. Physiological regulation of the transport activity in the uncoupling proteins UCP1 and UCP2.
    Biochim Biophys Acta. 2001 Mar 1;1504(1):70-81 PMID: 11239486
  14. The mitochondrial calcium uniporter is a highly selective ion channel.
    Nature. 2004 Jan 22;427(6972):360-4 PMID: 14737170
  15. Fatty acids are rapidly delivered to and extracted from membranes by methyl-beta-cyclodextrin.
    J Lipid Res. 2010 Jan;51(1):120-31 PMID: 19625735
  16. Listening to neurotransmitter transporters.
    Neuron. 1996 Nov;17(5):807-10 PMID: 8938113
  17. Enzymatic properties of human cytosolic phospholipase A(2)gamma.
    J Biol Chem. 2002 Aug 16;277(33):29526-36 PMID: 12039969
  18. Transport Properties for Aqueous Sodium Sulfonate Surfactants.
    J Colloid Interface Sci. 1999 Aug 1;216(1):16-24 PMID: 10395757
  19. Reconstitution of recombinant uncoupling proteins: UCP1, -2, and -3 have similar affinities for ATP and are unaffected by coenzyme Q10.
    J Biol Chem. 2003 Jul 11;278(28):25825-31 PMID: 12734183
  20. The uncoupling protein from brown fat mitochondria is related to the mitochondrial ADP/ATP carrier. Analysis of sequence homologies and of folding of the protein in the membrane.
    EMBO J. 1985 Sep;4(9):2369-76 PMID: 3000775
  21. Activity of phospholipase A2 in the inner membrane of rat-liver mitochondria.
    Eur J Biochem. 1981 Oct;119(3):517-21 PMID: 7308197
  22. Alkylsulfonates activate the uncoupling protein UCP1: implications for the transport mechanism.
    Biochim Biophys Acta. 2004 Feb 15;1608(2-3):122-30 PMID: 14871489
  23. 108-pS channel in brown fat mitochondria might Be identical to the inner membrane anion channel.
    J Biol Chem. 1997 Aug 1;272(31):19282-9 PMID: 9235923
  24. Structure and function of the uncoupling protein from brown adipose tissue.
    Biochim Biophys Acta. 1999 Jan 8;1415(2):271-96 PMID: 9889383
  25. Identification of calcium-independent phospholipase A2gamma in mitochondria and its role in mitochondrial oxidative stress.
    Am J Physiol Renal Physiol. 2007 Feb;292(2):F853-60 PMID: 17047165
  26. Interactions of lyso 1-palmitoylphosphatidylcholine with phospholipids: a 13C and 31P NMR study.
    Biochemistry. 1995 Apr 25;34(16):5666-77 PMID: 7727427
  27. Complete nucleotide and derived amino acid sequence of cDNA encoding the mitochondrial uncoupling protein of rat brown adipose tissue: lack of a mitochondrial targeting presequence.
    Nucleic Acids Res. 1986 May 27;14(10):4025-35 PMID: 3012461
  28. Recent progress in phospholipase A₂ research: from cells to animals to humans.
    Prog Lipid Res. 2011 Apr;50(2):152-92 PMID: 21185866
  29. Making heads or tails of phospholipids in mitochondria.
    J Cell Biol. 2011 Jan 10;192(1):7-16 PMID: 21220505
  30. The voltage sensor in voltage-dependent ion channels.
    Physiol Rev. 2000 Apr;80(2):555-92 PMID: 10747201
  31. Brown adipose tissue: function and physiological significance.
    Physiol Rev. 2004 Jan;84(1):277-359 PMID: 14715917
  32. Brown-adipose-tissue mitochondria: the regulation of the 32000-Mr uncoupling protein by fatty acids and purine nucleotides.
    Eur J Biochem. 1983 Dec 1;137(1-2):197-203 PMID: 6317384
  33. New substrates and competitive inhibitors of the Cl- translocating pathway of the uncoupling protein of brown adipose tissue mitochondria.
    J Biol Chem. 1990 Nov 5;265(31):19303-11 PMID: 2229077
  34. Evidence for two distinct chloride uniport pathways in brown adipose tissue mitochondria.
    Am J Physiol. 1989 Dec;257(6 Pt 1):C1142-8 PMID: 2481977
  35. Ultrastructural and biochemical studies of mitoplasts and outer membranes derived from French-pressed mitochondria. Advances in mitochondrial subfractionation.
    J Ultrastruct Res. 1977 Apr;59(1):44-56 PMID: 850300
  36. Native UCP1 displays simple competitive kinetics between the regulators purine nucleotides and fatty acids.
    J Biol Chem. 2004 Sep 10;279(37):38236-48 PMID: 15208325
  37. Brown-adipose-tissue mitochondria: photoaffinity labelling of the regulatory site of energy dissipation.
    Eur J Biochem. 1978 Jan 16;82(2):515-21 PMID: 624284
  38. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese.
    Nature. 1997 May 1;387(6628):90-4 PMID: 9139827
  39. Fatty acid transport: difficult or easy?
    J Lipid Res. 1998 Mar;39(3):467-81 PMID: 9548581
  40. The pKa values of PFOA and other highly fluorinated carboxylic acids.
    Environ Sci Technol. 2008 Jan 15;42(2):456-8 PMID: 18284146
  41. Effect of fatty acids on H+ transport activity of the reconstituted uncoupling protein.
    J Biol Chem. 1994 Jan 28;269(4):2508-15 PMID: 8300577
  42. Complete cDNA-derived amino acid sequence of rat brown fat uncoupling protein.
    J Biol Chem. 1986 Feb 5;261(4):1487-90 PMID: 3753702
  43. Electrophysiological insights into the mechanism of ion-coupled cotransporters.
    News Physiol Sci. 2004 Apr;19:80-4 PMID: 15016908
  44. Structure of a eukaryotic CLC transporter defines an intermediate state in the transport cycle.
    Science. 2010 Oct 29;330(6004):635-41 PMID: 20929736
  45. Interfacial kinetic and binding properties of mammalian group IVB phospholipase A2 (cPLA2beta) and comparison with the other cPLA2 isoforms.
    J Biol Chem. 2010 Nov 12;285(46):36100-11 PMID: 20705608
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2012.09.010
Published
2012-10-12
Pages
400-13
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3782081
Subset
IM
Grants
NIH HHS · DP2 OD004656 · United States
NIH HHS · DP2OD004656 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2012.09.010 PMC Full Text View journal details
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