Intrinsic and extrinsic uncoupling of oxidative phosphorylation.
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 DeltaPsi, 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 DeltaPsi and maintains high DeltaPsi values (150-200 mV). The second occurs only in mitochondria, is suggested to keep DeltaPsi 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 DeltaPsi and the production of reactive oxygen species (ROS) in mitochondria at high DeltaPsi values (150-200 mV) are discussed.
Kadenbach
Bernhard
B
Fachbereich Chemie, Philipps-Universität, Hans-Meerwein-Strasse, D-35032 Marburg, Germany. Kadenbach@chemie.uni-marburg.de
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005075:Biological Evolution; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D010085:Oxidative Phosphorylation / Q000187:drug effects; D017494:Proton Pumps / Q000187:drug effects / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000378:metabolism; D011522:Protons; D017382:Reactive Oxygen Species / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism; D014475:Uncoupling Agents / Q000378:metabolism* / Q000494:pharmacology
D005227:Fatty Acids; D008565:Membrane Proteins; D017494:Proton Pumps; D011522:Protons; D017382:Reactive Oxygen Species; D013963:Thyroid Hormones; D014475:Uncoupling Agents; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D006180:Proton-Translocating ATPases