Skip to main content
NCBI home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1990 Jul;87:213–218. doi: 10.1289/ehp.9087213

Uncouplers of oxidative phosphorylation.

H Terada 1
PMCID: PMC1567840  PMID: 2176586

Abstract

Uncouplers of oxidative phosphorylation in mitochondria inhibit the coupling between the electron transport and phosphorylation reactions and thus inhibit ATP synthesis without affecting the respiratory chain and ATP synthase (H(+)-ATPase). Miscellaneous compounds are known to be uncouplers, but weakly acidic uncouplers are representative because they show very potent activities. The most potent uncouplers discovered so far are the hindered phenol SF 6847, and hydrophobic salicylanilide S-13, which are active in vitro at concentrations in the 10 nM range. For induction of uncoupling, an acid dissociable group, bulky hydrophobic moiety and strong electron-withdrawing group are required. Weakly acidic uncouplers are considered to produce uncoupling by their protonophoric action in the H(+)-impermeable mitochondrial membrane. For exerting these effects, the stability of the respective uncoupler anions in the hydrophobic membrane is very important. High stability is achieved by delocalization of the polar ionic charge through uncoupler (chemical)-specific mechanisms. Such an action of weakly acidic uncouplers is characteristic of the highly efficient membrane targeting action of a nonsite-specific type of bioactive compound.

Full text

PDF
213

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Cantley L. C., Jr, Hammes G. G. Activation of beef heart mitochondrial adenosine triphosphatase by 2,4-dinitrophenol. Biochemistry. 1973 Nov 20;12(24):4900–4904. doi: 10.1021/bi00748a014. [DOI] [PubMed] [Google Scholar]
  2. Dabadie P., Bendriss P., Erny P., Mazat J. P. Uncoupling effects of local anesthetics on rat liver mitochondria. FEBS Lett. 1987 Dec 21;226(1):77–82. doi: 10.1016/0014-5793(87)80554-9. [DOI] [PubMed] [Google Scholar]
  3. Garlid K. D., Nakashima R. A. Studies on the mechanism of uncoupling by amine local anesthetics. Evidence for mitochondrial proton transport mediated by lipophilic ion pairs. J Biol Chem. 1983 Jul 10;258(13):7974–7980. [PubMed] [Google Scholar]
  4. Hanstein W. G., Hatefi Y. Trinitrophenol: a membrane-impermeable uncoupler of oxidative phosphorylation. Proc Natl Acad Sci U S A. 1974 Feb;71(2):288–292. doi: 10.1073/pnas.71.2.288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Hanstein W. G., Kiehl R. Energy-dependent accumulation of the uncoupler picrate and proton flux in submitochondrial particles. Biochem Biophys Res Commun. 1981 Jun 16;100(3):1118–1125. doi: 10.1016/0006-291x(81)91939-2. [DOI] [PubMed] [Google Scholar]
  6. Hanstein W. G. Uncoupling of oxidative phosphorylation. Biochim Biophys Acta. 1976 Sep 27;456(2):129–148. doi: 10.1016/0304-4173(76)90010-0. [DOI] [PubMed] [Google Scholar]
  7. McLaughlin S. G., Dilger J. P. Transport of protons across membranes by weak acids. Physiol Rev. 1980 Jul;60(3):825–863. doi: 10.1152/physrev.1980.60.3.825. [DOI] [PubMed] [Google Scholar]
  8. Muraoka S., Terada H. 3,5-di-tert-butyl-4-hydroxybenzylidenemalononitrile; a new powerful uncoupler of respiratory-chain phosphorylation. Biochim Biophys Acta. 1972 Aug 17;275(2):271–275. doi: 10.1016/0005-2728(72)90047-3. [DOI] [PubMed] [Google Scholar]
  9. Shinohara Y., Terada H. Possible involvement of the 29 kDa protein in H+-ATPase in the action of cationic uncoupler of oxidative phosphorylation. Effect of the (o-phenanthroline)2-Cu2+ complex as a cationic uncoupler. Biochim Biophys Acta. 1987 Mar 4;890(3):387–391. doi: 10.1016/0005-2728(87)90167-8. [DOI] [PubMed] [Google Scholar]
  10. Terada H., Fukui Y., Shinohara Y., Ju-ichi M. Unique action of a modified weakly acidic uncoupler without an acidic group, methylated SF 6847, as an inhibitor of oxidative phosphorylation with no uncoupling activity: possible identity of uncoupler binding protein. Biochim Biophys Acta. 1988 Mar 30;933(1):193–199. doi: 10.1016/0005-2728(88)90070-9. [DOI] [PubMed] [Google Scholar]
  11. Terada H., Goto S., Yamamoto K., Takeuchi I., Hamada Y., Miyake K. Structural requirements of salicylanilides for uncoupling activity in mitochondria: quantitative analysis of structure-uncoupling relationships. Biochim Biophys Acta. 1988 Dec 7;936(3):504–512. doi: 10.1016/0005-2728(88)90027-8. [DOI] [PubMed] [Google Scholar]
  12. Terada H., Kubota S. Does hydrophobic isothiocyanate really uncouple oxidative phosphorylation in mitochondria? Uncoupling activity of a product of isothiocyanate in dimethylsulfoxide solution. FEBS Lett. 1979 Apr 1;100(1):37–40. doi: 10.1016/0014-5793(79)81126-6. [DOI] [PubMed] [Google Scholar]
  13. Terada H., Nagamune H., Morikawa N., Ikuno M. Uncoupling of oxidative phosphorylation by divalent cationic cyanine dye. Participation of phosphate transporter. Biochim Biophys Acta. 1985 May 3;807(2):168–176. doi: 10.1016/0005-2728(85)90120-3. [DOI] [PubMed] [Google Scholar]
  14. Terada H. The interaction of highly active uncouplers with mitochondria. Biochim Biophys Acta. 1981 Dec 30;639(3-4):225–242. doi: 10.1016/0304-4173(81)90011-2. [DOI] [PubMed] [Google Scholar]
  15. Terada H., VAN Dam K. On the stoichiometry between uncouplers of oxidative phosphorylation and respiratory chains. The catalytic action of SF 6847 (3,5-di-tert-butyl-4-hydroxy-benzylidenemalononitrile). Biochim Biophys Acta. 1975 Jun 17;387(3):507–518. doi: 10.1016/0005-2728(75)90089-4. [DOI] [PubMed] [Google Scholar]
  16. Williamson R. L., Metcalf R. L. Salicylanilides: a new group of active uncouplers of oxidative phosphorylation. Science. 1967 Dec 29;158(3809):1694–1695. doi: 10.1126/science.158.3809.1694. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES