Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The widespread occurrence of excess weight and related diseases demands that efforts be made to understand energy expenditure from the gene to the whole animal. For some time, it has been understood that mitochondrial oxidation of fuels generates an electrochemical gradient via outward pumping of protons by the electron transport chain. ATP production via F(1)F(0) ATP synthase is then facilitated by the inward flux of protons down the gradient. There is a growing appreciation that a significant portion of the metabolic rate of endotherms is attributable to counteracting "proton leak" (uncoupling), wherein a flux of protons down the electrochemical gradient generates heat independently of ATP production. Proton leak is especially apparent in thermogenic brown adipose tissue, which expresses a tissue-specific uncoupling protein (UCP1). The recent discovery of widely expressed putative UCP1 homologs [UCP2, UCP3, UCP4, UCP5/brain mitochondrial carrier protein-1 (BMCP1)] raised the possibility that innate proton leak and metabolic rate are regulated by UCP1-like proteins. On the basis of current published data, one may not exclude the possibility that UCP homologs influence metabolic rate.
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PMID:Uncoupling protein homologs: emerging views of physiological function. 1073 18

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.
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PMID:Intrinsic and extrinsic uncoupling of oxidative phosphorylation. 1276 65

Instead of a comprehensive review, we describe the basic undisputed facts and a modest contribution of our group to the fascinating area of the research on mitochondrial uncoupling proteins. After defining the terms uncoupling, leak, protein-mediated uncoupling, we discuss the assumption that due to their low abundance the novel mitochondrial uncoupling proteins (UCP2 to UCP5) can provide only a mild uncoupling, i.e. can decrease the proton motive force by several mV only. Contrary to this, the highly thermogenic role of UCP1 in brown adipose tissue is not given only by its high content (approximately 5 % of mitochondrial proteins) but also by the low ATP synthase content and high capacity respiratory chain. Fatty acid cycling mechanism as a plausible explanation for the protonophoretic function of all UCPs and some other mitochondrial carriers is described together with the experiments supporting it. The phylogenesis of all UCPs, estimated UCP2 content in several tissues, and details of UCP2 activation are described on the basis of our experiments. Functional activation of UCP2 is proposed to decrease reactive oxygen species (ROS) production. Moreover, reaction products of lipoperoxidation such as cleaved hydroperoxy-fatty acids and hydroxy-fatty acid can activate UCP2 and promote feedback down-regulation of mitochondrial ROS production.
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PMID:Mitochondrial uncoupling proteins--facts and fantasies. 1511 50