Uncoupling proteins and mitochondrial function. The figure shows key proteins in the inner mitochondrial membrane involved in mitochondrial respiration, oxidative phosphorylation, uncoupling, and import of long-chain acyl-CoA molecules. Two potential roles for UCP3 function are illustrated. (right-hand side) UCP3 functions as an uncoupler by acting as a channel for proton entry into the matrix, which dissipates the transmembrane potential generated by respiratory chain complexes I through IV. This reduces the motive force for proton entry via the F₁F₀-ATPase, which catalyzes ATP synthesis, and, in effect, uncouples respiration from oxidative phosphorylation. Substrate oxidation proceeds via transfer of electrons from donors (reductants) to acceptors (oxidants) along the respiratory chain to water, releasing energy as heat. Another consequence is a reduction in reactive oxygen species formation, since these species are generated under conditions of high transmembrane potential and electron flow. (left-hand side) In another scenario, UCP3 acts as an exporter of fatty acid anions (FA^-). This could facilitate fatty acid oxidation and explain experimental observations linking regulation of UCP3 expression and genetic variation with effects on fat oxidation. Under conditions of high fatty acid flux into mitochondria via carnitine palmitoyltransferase 1 (CPT1), excessive accumulation of long chain acyl-CoA molecules would be harmful to membranes and sequester CoA, thereby impairing fat oxidation. To prevent these events, upregulation of mitochondrial thioesterase cleaves the acyl-CoA allowing export of the fatty acid anion via UCP3. Reuptake of a neutral fatty acid could deliver the proton (plus fatty acid anion) back into the matrix resulting in uncoupling; however, the fatty acid export function would not necessarily depend upon an uncoupling action for UCP3. e^-, electron; I, Complex I or NADH-ubiquinone oxidoreductase; II, Complex II or succinate ubiquinone oxidoreductase; III, Complex III or ubiquinol-cytochrome c oxidoreductase; IV, Complex IV or cytochrome c oxidase; Q, coenzyme Q or ubiquinone; c, cytochrome c; UQ•^–, ubisemiquinone; O2•^–, superoxide; ROS, reactive oxygen species; SOD, superoxide dismutase; F₁ is the water-soluble nucleotide-binding complex and F₀ is the hydrophobic transmembrane complex that together comprise the F₁F₀-ATPase.