Intrinsic and extrinsic uncoupling of oxidative phosphorylation |
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Authors: | Bernhard Kadenbach |
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Institution: | Fachbereich Chemie, Philipps-Universität, Hans-Meerwein-Strasse, D-35032 Marburg, Germany |
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Abstract: | This article reviews parameters of extrinsic uncoupling of oxidative phosphorylation (OxPhos) in mitochondria, based on induction of a proton leak across the inner membrane. The effects of classical uncouplers, fatty acids, uncoupling proteins (UCP1-UCP5) and thyroid hormones on the efficiency of OxPhos are described. Furthermore, the present knowledge on intrinsic uncoupling of cytochrome c oxidase (decrease of H+/e− stoichiometry=slip) is reviewed. Among the three proton pumps of the respiratory chain of mitochondria and bacteria, only cytochrome c oxidase is known to exhibit a slip of proton pumping. Intrinsic uncoupling was shown after chemical modification, by site-directed mutagenesis of the bacterial enzyme, at high membrane potential ΔΨ, and in a tissue-specific manner to increase thermogenesis in heart and skeletal muscle by high ATP/ADP ratios, and in non-skeletal muscle tissues by palmitate. In addition, two mechanisms of respiratory control are described. The first occurs through the membrane potential ΔΨ and maintains high ΔΨ values (150-200 mV). The second occurs only in mitochondria, is suggested to keep ΔΨ at low levels (100-150 mV) through the potential dependence of the ATP synthase and the allosteric ATP inhibition of cytochrome c oxidase at high ATP/ADP ratios, and is reversibly switched on by cAMP-dependent phosphorylation. Finally, the regulation of ΔΨ and the production of reactive oxygen species (ROS) in mitochondria at high ΔΨ values (150-200 mV) are discussed. |
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Keywords: | Uncoupling of oxidative phosphorylation Proton pumping Membrane potential Cytochrome c oxidase ROS production Thyroid hormone Protein phosphorylation ATP synthase |
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