Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The reduction of molecular oxygen to water provides most of the biologically useful energy. However, oxygen reduction is a mixed blessing because incompletely reduced oxygen species such as superoxide or peroxides are quite reactive and can, when out of control, cause damage. In mitochondria, where most of the oxygen utilized by eukaryotic cells is reduced, the dichotomy of oxygen shows itself best. Thus, reactive oxygen is a threat to them, as is evident from oxidative damage to mitochondrial lipids, proteins, and nucleic acids. Reactive oxygen, in the form of peroxides, also serves useful functions in mitochondria. This is exemplified by the control of mitochondrial and cellular calcium homeostasis, whose understanding has improved greatly during the last few years. An exciting new aspect is the discovery that nitric oxide and congeners have an enormous impact on mitochondria. Physiological concentrations of nitrogen monoxide (NO) at physiological cellular oxygen pressure inhibit cytochrome oxidase and thereby respiration. A transient inhibition of cytochrome oxidase by NO appears to be used in at least some forms of cell signalling. Peroxynitrite, the product of the reaction between superoxide and NO, can stimulate the specific calcium release pathway from mitochondria by oxidizing some vicinal thiols in mitochondria. There is evidence mounting that mitochondrial calcium handling and its modulation by reactive oxygen and nitrogen species is important for necrotic and apoptotic cell death.
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PMID:Reactive oxygen and nitrogen species regulate mitochondrial Ca2+ homeostasis and respiration. 917 21

The influence of nitric oxide on mitochondrial permeability transition (MPT) phenomenon was studied. NO was generated by photolysis of S-nitroso-N-acetylcysteine, AcCys(NO), with green light (lambda = 550 nm). Two distinct effects of nitric oxide on rat liver mitochondria were identified. First, NO accelerated an onset of swelling in Ca2(+)-loaded mitochondria in a cyclosporin-A-sensitive manner acting as an inducer of permeability transition. This was, apparently, a result of irreversible alteration of mitochondrial function accompanying the inhibition of respiratory chain in the presence of calcium. Formation of ESR-visible iron-sulfur dinitrosyl complexes (g = 2.041) could also contribute to the irreversible changes resulting in MPT induction. Second, NO changed significantly the response of mitochondria to Ca2+/phosphate-induced MPT, acting as a regulator of permeability transition. In this case the action of nitric oxide led to division of the mitochondria into two subpopulations: one which underwent the rapid permeability transition and another in which the MPT was inhibited. The effect of NO on Ca2+/Pi-induced MPT was transient and resulted from reversible inhibition of cytochrome oxidase followed by the changes in transmembrane potential and Ca2+ distribution. The characteristic time of duration of these NO modulated effects depended on nitric oxide as well as on oxygen concentrations. With increasing NO at fixed oxygen concentrations, this time levelled off to reach a maximum value which was inversely related to the oxygen concentration. It is concluded that under physiological condition the duration of reversible NO effects on mitochondrial function could be determined by oxygen concentration.
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PMID:Modulation of the mitochondrial permeability transition by nitric oxide. 921 30

Peroxynitrite anion, the reaction product of superoxide and nitric oxide, is a potent biological oxidant, which inactivates mammalian heart mitochondrial NADH-coenzyme Q reductase (complex I), succinate dehydrogenase (complex II), and ATPase, without affecting cytochrome c oxidase (complex IV). In this paper, we evaluated the effect of peroxynitrite on mitochondrial membrane integrity and permeability under low calcium concentration. Phosphate buffer was used in most of our experiments since Hepes, Tris, mannitol, and sucrose were found to inhibit the oxidative chemistry of peroxynitrite. Peroxynitrite (0.1-1.0 mM) caused a dose-dependent decrease in the ability of mitochondria to build up a membrane potential when N,N,N',N'-tetramethyl-p-phenylenediamine/ascorbate were used as substrate. Elimination of the membrane potential was accompanied by penetration of the osmotic support (KCl/NaCl) into the matrix as judged by the parallel occurrence of mitochondrial swelling. This swelling was partially inhibited by dithiothreitol (DTT) or butylated hydroxytoluene (BHT) and was insensitive to ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, ADP, and cyclosporin A. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of solubilized membrane proteins indicated that alterations in membrane permeability were associated with the production of protein aggregates due to membrane protein thiol cross-linking. The protective effect of DTT on both mitochondrial swelling and protein polymerization suggests the involvement of disulfide bonds in the membrane permeabilization process. In addition, the increase in thiobarbituric acid-reactive substances and the partial inhibitory effect of BHT indicate the occurrence of lipid peroxidation. These results support the idea that under our experimental conditions peroxynitrite causes mitochondrial structural and functional alterations by Ca2+-independent mechanisms through lipid peroxidation and protein sulfhydryl oxidation.
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PMID:Ca2+-independent permeabilization of the inner mitochondrial membrane by peroxynitrite is mediated by membrane protein thiol cross-linking and lipid peroxidation. 930 96

Nitric oxide (NO) at high levels is cytotoxic, and may be involved in a range of inflammatory, neurodegenerative, and cardiovascular/ischaemic pathologies. The mechanism of NO-induced cytotoxicity is unclear. Recently we and others have found that low (nanomolar) levels of NO reversibly inhibit mitochondrial respiration by binding to the oxygen binding site of cytochrome oxidase in competition with oxygen. This raises the apparent K(m) for oxygen of mitochondrial respiration into the physiological range, potentially making respiration sensitive to the oxygen level. The NO inhibition of oxygen consumption was seen in isolated cytochrome oxidase, mitochondria, brain nerve terminals, and cultured cells. Cultured astrocytes activated to express the inducible from of NO synthase produced up to 1 microM NO and strongly inhibited their own cellular respiration rate. This respiratory inhibition was rapidly reversed by removing the NO, and was due to the inhibition of cytochrome oxidase. These results suggest that any cell producing high levels of NO will inhibit its own respiration and that of surrounding cells, and make the respiration rate sensitive to the oxygen level. This inhibition of energy metabolism may contribute to cytotoxicity or cytostasis in some pathologies.
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PMID:Nitric oxide inhibition of cytochrome oxidase and mitochondrial respiration: implications for inflammatory, neurodegenerative and ischaemic pathologies. 930 86

Within the central nervous system, nitric oxide is an important physiological messenger. However, when synthesized excessively in neurones, cell death may occur. An impairment of mitochondrial cytochrome oxidase and subsequent cellular energy depletion seems to be a likely mechanism for this neurotoxicity. Within neurones, nitric oxide is synthesized by the constitutive, Ca(2+)-dependent form of nitric oxide synthase (nNOS). Astrocytes, however, possess both the constitutive and the inducible Ca(2+)-independent NOS (iNOS), which is expressed by endotoxin and/or cytokines. In vitro, activation of nNOS rapidly produces neuronal cell death. In contrast to neurones, following induction of iNOS, astrocytes synthesize large quantities of nitric oxide, but cell death is not apparent despite marked damage to mitochondrial cytochrome oxidase. The resistance of astrocytes to nitric oxide synthase-mediated cell damage may be due to their ability to increase their glycolytic rate when mitochondrial ATP synthesis is compromised. On the basis of this phenomenon, we propose that activated astrocytes represent a suitable system for studying the efficacy of potential therapeutic agents at protecting from nitric oxide synthase-mediated mitochondrial damage.
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PMID:Evaluation of the efficacy of potential therapeutic agents at protecting against nitric oxide synthase-mediated mitochondrial damage in activated astrocytes. 938 63

Previously, we found that cytochrome oxidase-rich zones in the supragranular layers of the macaque striate cortex had more asymmetric, glutamate-immunoreactive synapses than the surrounding, cytochrome oxidase-poor regions. A major glutamate receptor family is N-methyl-D-aspartate, which is implicated in the stimulation of nitric oxide synthase and in the production of nitric oxide, a gaseous intra- and inter-cellular messenger. To determine if energy-generating and energy-utilizing enzymes bore any spatial relationship with neurochemicals associated with glutamatergic neurotransmission in the monkey visual cortex, serial cortical sections were processed histochemically for cytochrome oxidase and NADPH-diaphorase, and immunohistochemically for sodium/potassium-ATPase, nitric oxide synthase, and N-methyl-D-aspartate receptor subunit 1 protein, respectively. The general patterns were similar among the five neurochemicals, with layers 4C, 6 and supragranular puffs being labelled, although the intensity of labelling differed among them. Monocular impulse blockade with tetrodotoxin for two to four weeks induced a down-regulation of all five neurochemicals not only in deprived layer 4C ocular dominance columns, but also in deprived rows of puffs. Thus, the regulation of all five neurochemicals in the mature visual cortex is activity-dependent. Combined cytochrome oxidase histochemistry and nitric oxide synthase immunohistochemistry in the same sections revealed that double-labelled cells were primarily medium-sized non-pyramidals in various cortical layers. Likewise, those that were double-labelled by N-methyl-D-aspartate receptor subunit 1 immunohistochemistry and nitric oxide synthase immunogold silver staining in the same sections were of the medium-sized non-pyramidal neurons. At the ultrastructural level, combined cytochrome oxidase cytochemistry and postembedding immunogold labelling for nitric oxide synthase showed that immunogold particles for nitric oxide synthase were more heavily concentrated in cytochrome oxidase-rich type C cells. These medium-sized non-pyramidal cells were previously found to be gamma aminobutyric acid-immunoreactive and received both gamma aminobutyric acid- and glutamate-immunoreactive axosomatic synapses. Thus, our results are consistent with an enrichment of excitatory synaptic interactions in metabolically active regions of the primate visual cortex that involves glutamate-related neurochemicals, such as N-methyl-D-aspartate receptors and nitric oxide synthase. These interactions impose a higher energy demand under normal conditions and are down-regulated by retinal impulse blockade.
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PMID:Neurochemical organization of the macaque striate cortex: correlation of cytochrome oxidase with Na+K+ATPase, NADPH-diaphorase, nitric oxide synthase, and N-methyl-D-aspartate receptor subunit 1. 950 44

The possible role of nitric oxide (.NO) in brain energy metabolism during perinatal asphyxia in the rat was studied. Exposure of early neonates to 5 min of anoxia significantly inhibited brain mitochondrial complex II-III activity by 25%, without affecting complex I, complex IV or citrate synthase activities. This insult was accompanied by ATP depletion (54%) and increased concentration of nitrites plus nitrates (1.4-fold), suggesting enhanced .NO synthesis. Administration of Nomega-nitro-L-arginine monomethyl ester (L-NAME) to the mothers inhibited neonatal brain .NO synthase activity, as reflected by the decreased (23%) cyclic GMP concentration. These L-NAME-treated neonates showed complete resistance to anoxic-mediated brain mitochondrial complex II-III damage. Our results suggest that brain mitochondrial dysfunction leading to energy deficiency during perinatal asphyxia is a .NO-mediated process.
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PMID:Nitric oxide mediates brain mitochondrial damage during perinatal anoxia. 951 75

We determined the ability of pathological levels of nitric oxide (NO) to cause glutamate release from isolated rat brain nerve terminals using a fluorometric assay. It was found that NO (0.7 and 2 microM) produced (4 and 10 nmol/mg of synaptosomal protein) Ca2+-independent glutamate release from synaptosomes (after 1 min of exposure). Spermine/NO complex (spermine NONOate; a slow NO donor) and potassium cyanide (an inhibitor of cytochrome oxidase) also caused Ca2+-independent glutamate release. Preincubation of synaptosomes with 5 microM 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (an inhibitor of soluble guanylyl cyclase) had no effect on NO-induced Ca2+-independent glutamate release. Ca2+-independent glutamate release produced by NO was greater in a low-oxygen medium. NO, spermine NONOate, and potassium cyanide inhibited synaptosomal respiration with a similar order of potency with respect to their ability to cause glutamate release. Because NO has been shown previously to inhibit reversibly cytochrome oxidase in competition with oxygen, our findings in this study suggest that NO (and cyanide) causes glutamate release following inhibition of mitochondrial respiration at the level of cytochrome oxidase. Thus, elevated NO production leading to mitochondrial dysfunction, glutamate release, and excitotoxicty may contribute to neuronal death in neurological diseases.
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PMID:Nitric oxide causes glutamate release from brain synaptosomes. 952 71

The orientation dependence of the EPR signals arising from the azide-nitric oxide complex of cytochrome oxidase was investigated using oriented multilayers of mitochondrial membranes from ox heart. Variations in line shape of the DeltaMS=1 signal of the triplet state were apparent, whilst the DeltaMS=2 transitions between g=4.7 and 3.9 varied in intensity as the angle of the applied magnetic field was varied. These half-field signals were maximal with the field parallel to the membrane plane. A model of the bi-liganded azide-nitric oxide complex has been constructed, in which the nitric oxide is bound to the high-spin haem in a bent configuration, with the Fe-N=O plane at 60-90 degrees to the membrane plane and the azide bound to the copper, distal from the haem. In addition, angular variations of the signals at g'=11 and g' around 3.5, derived from an integer-spin complex, were also observed.
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PMID:Angular dependence of electron paramagnetic resonances of an azide-NO complex of cytochrome c oxidase: orientation of the haem-copper axis in cytochrome aa3 from ox heart. 955 53

Both reversible and irreversible inhibition of mitochondrial respiration have been reported following the generation of nitric oxide (NO) by cells. Using J774 cells, we have studied the effect of long-term exposure to NO on different enzymes of the respiratory chain. Our results show that, although NO inhibits complex IV in a way that is always reversible, prolonged exposure to NO results in a gradual and persistent inhibition of complex I that is concomitant with a reduction in the intracellular concentration of reduced glutathione. This inhibition appears to result from S-nitrosylation of critical thiols in the enzyme complex because it can be immediately reversed by exposing the cells to high intensity light or by replenishment of intracellular reduced glutathione. Furthermore, decreasing the concentration of reduced glutathione accelerates the process of persistent inhibition. Our results suggest that, although NO may regulate cell respiration physiologically by its action on complex IV, long-term exposure to NO leads to persistent inhibition of complex I and potentially to cell pathology.
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PMID:Persistent inhibition of cell respiration by nitric oxide: crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione. 963 1


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