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An uncoupler or uncoupling agent is a molecule that disrupts oxidative phosphorylation in prokaryotes and mitochondria or photophosphorylation in chloroplasts and cyanobacteria by dissociating the reactions of ATP synthesis from the electron transport chain. The result is that the cell or mitochondrion expends energy to generate a proton motive force, but the proton motive force is dissipated before the ATP synthase can recapture this energy and use it to make ATP. Uncouplers are capable of transporting protons through mitochondrial and lipid membranes.


Classical uncouplers have five properties:[1]

  1. the complete release of respiratory control
  2. the substitution of all coupled processes (ATP synthesis, transhydrogenation, reverse electron flow, active transport of cations, etc.) by a cyclic proton transport mediated by the uncoupler
  3. the elimination of all protonic and cationic gradients generated across the mitochondrial or prokaryotic membrane
  4. no discrimination in these actions between one coupling site and another
  5. no discrimination between coupled processes driven by electron transfer and coupled processes driven by ATP hydrolysis

Pseudo-uncouplers show one or more of these properties, but not all, and thus must be combined with one or more other pseudo-uncouplers to achieve full uncoupling.[1]

Classical Uncouplers

The following compounds are known to be classical uncouplers:[1][2]


The following compounds are known to be pseudo-uncouplers:[1][2]

See also


  1. Not to be confused with the recreation drug, phencyclidine.


  1. 1.0 1.1 1.2 1.3 Kessler RJ, Tyson CA, Green DE. (1976). "Mechanism of uncoupling in mitochondria: Uncouplers as ionophores for cycling cations and protons". Proc Natl Acad Sci USA 73 (9): 3141–3145. doi:10.1073/pnas.73.9.3141. PMID 9641. PMC 430958. 
  2. 2.0 2.1 Childress ES, Alexopoulos SJ, Hoehn KS, Santos WL. (2018). "Small Molecule Mitochondrial Uncouplers and Their Therapeutic Potential". J Med Chem 61 (11): 4641–4655. doi:10.1021/acs.jmedchem.7b01182. PMID 29156129. 

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