Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 aim of the present study was to evaluate if defects of the respiratory chain known to occur in humans, also exist in lower primates. Cytochemical-immunocytochemical studies of the respiratory chain enzymes in five monkeys (10-25 years of age) showed defects of ubiquinone cytochrome-c-oxidoreductase (complex III), of cytochrome-c-oxidase (complex IV) and of ATP-synthase (complex V) in the limb muscles, diaphragm, heart muscle and extraocular muscles of three old animals (about 25 years) and also in the heart muscle of two younger animals (10 and 15 years). Characteristically, the defects were randomly distributed and there was no loss of succinate-dehydrogenase (complex II) in the fibres. Ultracytochemistry-immunocytochemistry of complex IV disclosed that in an involved fibre segment all the mitochondria exhibited the defect. The highest number of defects was observed in the extraocular muscle (up to 340/cm2) while the lowest defect density was present in the limb muscles (2-5/cm2). Defects of complex IV occurred two to three times more often than defects of complex III and besides isolated defects of complex III and IV, combined defects of both complexes were also observed. Defects of complex V occurred exclusively in combination and were rarely seen. Using subunit specific antisera against complex IV, it could be demonstrated at light and electron microscopic level that loss of activity of cytochrome-c-oxidase was associated with a loss both of mitochondrially and nuclearly coded subunits of the enzyme. In summary, aging in lower primates and humans is characterised by a highly similar defect expression of the respiratory chain enzymes, with intercellular and interorgan differences of the aging process, underlining the universal nature of the involved pathogenetic mechanisms.
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PMID:Defects of the respiratory chain in various tissues of old monkeys: a cytochemical-immunocytochemical study. 873 13

Midazolam, a water soluble benzodiazepine used as a preanaesthetic and hypnotic drug, showed a concentration-related (0.1-0.75 mM) depressant effect on both Adenosine 5'-diphosphate (ADP)-induced oxygen consumption and oxidative phosphorylation of rat liver mitochondria if the substrate was oxidized at different steps in the oxidation chain, but not when the substrate was ascorbate plus tetramethyl-p-phenylenediamine (complex IV). Furthermore, midazolam did not affect citrate synthase activity, but inhibited the 2,4 dinitrophenol (DNP)-uncoupled mitochondrial respiration. This result shows that midazolam primarily acts as a mitochondrial electron transport inhibitor. This inhibition is mainly due to the fact that midazolam decreases NADH ubiquinone reductase (complex I) and ubiquinol cytochrome c reductase (complex III) activities, but it also inhibits complex II activity. Spectrophotometric measurements of redox states of rat skeletal muscle mitochondria cytochromes show a decrease in the reduction of aa3 and c+c1 cytochromes in the presence of the benzodiazepine. Midazolam significantly decreased the reduced ubiquinone/total ubiquinone ratio (evaluated by means of HPLC and electrochemical detection) in rat liver mitochondria in both beta-hydroxybutyrate and succinate. Ubisemiquinone may be the redox component affected by midazolam, whether or not bound to the iron-sulfur proteins present in all three mitochondrial complexes. These effects of midazolam, not necessarily related to the preanaesthetic and hypnotic action are probably mediated via mitochondrial benzodiazepine receptors.
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PMID:Biochemical characterization of the effects of the benzodiazepine, midazolam, on mitochondrial electron transfer. 882 37

Dihydroorotate dehydrogenase (EC 1.3.3.1 or EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. In eukaryotes it is located in the inner mitochondrial membrane, with ubiquinone as the proximal and cytochrome oxidase as the ultimate electron transfer system, whereas the rest of pyrimidine biosynthesis takes place in the cytosol. Here, the distribution of dihydroorotate dehydrogenase activity in cryostat sections of various rat tissues, and tissue samples of human skin and kidney, was visualized by light microscopy using the nitroblue tetrazolium technique. In addition, a hydrogen peroxide-producing oxidase side-reactivity of dihydroorotate dehydrogenase could be visualized by trapping the peroxide with cerium-diaminobenzidine. The pattern of activity was similar to that of succinate dehydrogenase, but revealed a less intensive staining. High activities of dihydroorotate dehydrogenase were found in tissues with known proliferative, regenerative, absorptive or excretory activities, e.g., mucosal cells of the ileum and colon crypts in the gastrointestinal tract, cultured Ehrlich ascites tumor cells, and proximal tubules of the kidney cortex, whilst lower activities were present in the periportal area of the liver, testis and spermatozoa, prostate and other glands, and skeletal muscle. Dihydroorotate dehydrogenase and succinate dehydrogenase activity in Ehrlich ascites tumor cells grown in suspension culture were quantified by application of nitroblue tetrazolium or cyanotolyl tetrazolium and subsequent extraction of the insoluble formazans with organic solvents. The ratio of dihydroorotate dehydrogenase to succinate dehydrogenase activity was 1:4. This was in accordance with that of 1:5 obtained from oxygen consumption measurement of isolated mitochondria on addition of dihydroorotate or succinate. The ratio determined with mitochondria from animal tissues was up to 1:15 (rat liver, bovine heart). The application of the enzyme inhibitors brequinar sodium and toltrazuril verified the specificity of the histochemical and biochemical methods applied.
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PMID:Catalytic enzyme histochemistry and biochemical analysis of dihydroorotate dehydrogenase/oxidase and succinate dehydrogenase in mammalian tissues, cells and mitochondria. 885 33

The electron-transfer activities of bovine heart mitochondrial complexes I, II, and III, but not complex IV, were simultaneously inhibited by 2-alkyl-4,6-dinitrophenols to a different extent. The extent of inhibition of NADH and succinate oxidase activities by dinitrophenols was compared with that of individual complex activities using submitochondrial particles. The extent of inhibition of succinate oxidase activity by 1-methylpropyl and 1-methylbutyl derivatives was much larger than that of NADH oxidase activity. This large inhibition of succinate oxidase activity seemed not to be explainable by the extent of inhibition of individual complex activities (i.e., complexes II and III activities), based upon the homogeneous ubiquinone pool model. On the other hand, other dinitrophenols (n-propyl, 1-methylpentyl, 1-methylhexyl, and tert-butyl derivatives) very similar to the above compounds did not elicit such anomalous inhibitory action, indicating that the action of 1-methylpropyl and 1-methylbutyl derivatives is highly specific to their structure. The anomalous inhibition by these two compounds was also observed with the isolated succinate-cytochrome c oxidoreductase, in which there is no ubiquinone pool behavior [Rich, P.R. (1984) Biochim. Biophys. Acta 768, 53-79]. However, when the succinate-cytochrome c reductase of which the activity had been partially restored by adding phospholipid and exogenous quinone to the phospholipid- and ubiquinone-depleted succinate-cytochrome c reductase was assayed, the anomalous inhibitory action of interest was undetectable. These results indicated that electron-transfer between complexes II and III, which is mediated not only by free-form, but also by protein-bound ubiquinone, occurs in the mitochondrial membrane. The fact that the anomalous inhibition of succinate oxidase activity of submitochondrial particles was sensitive to changes in the external osmotic pressure which affected the total area of the particle supports this notion.
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PMID:Direct interaction between mitochondrial succinate-ubiquinone and ubiquinol-cytochrome c oxidoreductases probed by sensitivity to quinone-related inhibitors. 888 24

Molecular genetic, cytochemical and morphometric analyses have been performed on isolated oocytes from 41 women (27-39 years of age) in order to detect mutations of mitochondrial DNA (mtDNA), defects of the respiratory chain (ubiquinone-cytochrome-c-oxidoreductase = complex III; cytochrome-c-oxidase = complex IV) and alterations of mitochondrial volume during cellular ageing. Morphometric analyses showed an increase in mitochondrial numerical density with age from the mean values of 7.36 per micron2 and 6.97 per micron3 up to 30 years to 10.74 per micron2 and 11.66 per micron3 in the age group 31-40 years (P < 0.001). Similarly, an increase in the mitochondrial profile area from 0.074 per micron2 in the age group < 30 years to 0.101 per micron2 was noted in the fourth decade. The mitochondrial volume fraction was also significantly increased in the elder age group. Neither point mutations of mtDNA (nucleotide pairs 3243, 8344) nor the common deletion (4977 bp, nucleotide pairs 8482-13460) could be detected. In parallel, ultra- and immunocytochemical studies of the complexes III-IV failed to reveal functional defects. In conclusion there is an age-related increase in the volume fraction of the mitochondria which might reflect subtle changes in the oxidative phosphorylation capacity, but is not linked to mutations of mtDNA or functional defects of the respiratory chain enzymes in mature human oocytes from women of reproductive age.
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PMID:Morphological-cytochemical and molecular genetic analyses of mitochondria in isolated human oocytes in the reproductive age. 923 39

Mitochondria generate reactive oxygen species (ROS) as byproducts of molecular oxygen consumption in the electron transport chain. Most cellular oxygen is consumed in the cytochrome-c oxidase complex of the respiratory chain, which does not generate reactive species. The ubiquinone pool of complex III of respiration is the major site within the respiratory chain that generates superoxide anion as a result of a single electron transfer to molecular oxygen. Superoxide anion and hydrogen peroxide, derived from the former by superoxide dismutase, are precursor of hydroxyl radical through the participation of transition metals. Glutathione (GSH) in mitochondria is the only defense available to metabolize hydrogen peroxide. A small fraction of the total cellular GSH pool is sequestered in mitochondria by the action of a carrier that transports GSH from the cytosol to the mitochondrial matrix. Mitochondria are not only one of the main cellular sources of ROS, they also are a key target of ROS. Mitochondria are subcellular targets of cytokines, especially tumor necrosis factor (TNF); depletion of GSH in this organelle renders the cell more susceptible to oxidative stress originating in mitochondria. Ceramide generated during TNF signaling leads to increased production of ROS in mitochondria. Chronic ethanol-fed hepatocytes are selectively depleted of GSH in mitochondria due to a defective operation of the carrier responsible for transport of GSH from the cytosol into the mitochondrial matrix. Under these conditions, limitation of the mitochondrial GSH pool represents a critical contributory factor that sensitizes alcoholic hepatocytes to the prooxidant effects of cytokines and prooxidants generated by oxidative metabolism of ethanol. S-adenosyl-L-methionine prevents development of the ethanol-induced defect. The mitochondrial GSH carrier has been functionally expressed in Xenopus laevis oocytes microinjected with mRNA from rat liver. This critical carrier displays functional characteristics distinct from other plasma membrane GSH carriers, such as its ATP dependency, inhibitor specificity, and the size class of mRNA that encode the corresponding carrier, suggesting that the mitochondrial carrier of GSH is a gene product distinct from the plasma membrane transporters.
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PMID:GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect. 925 4

Defects of the respiratory chain are a typical feature of mitochondrial diseases and occur also during normal aging where they have been described in postmitotic tissues. The present study addresses the question of defect expression in the normal and cirrhotic liver. Randomly distributed defects of complex III (ubiquinone-cytochrome-c-oxidoreductase) and of complex IV (cytochrome-c-oxidase) of the respiratory chain have been detected with age-related increasing frequency both in normal and cirrhotic livers. No defects were present for complex II (succinate-dehydrogenase) and complex V (adenosine triphosphate-synthase) and in liver cell carcinomas. Sixty-one of 107 normal livers (57%) showed defects of the respiratory chain. The defects occurred in advanced age (over 50 years) in 87%. In contrast 50 of 64 cirrhotic livers (78%) had defects and approximately 60% occurred after age 50. The defects were caused by a loss of enzyme protein involving both nuclearly and mitochondrially coded subunits. Ninety-four percent of the defects (n = 275) involved complex IV selectively. In 4% selective defects of complex III were found and combined defects of both complexes occurred in only 2%. In situ hybridization and polymerase chain reaction (PCR) studies for the detection of the common deletion (4.977 bp) and of various point mutations of mitochondrial DNA (mtDNA) revealed no consistent molecular genetic abnormalities in microdissected respiratory chain defective liver cell areas. Single point mutations at nt 3243 and/or 5692 were found only in 7 of 18 microdissected probes from 6 patients. The results show that defects of the respiratory chain occur already in normal livers most probably during cell aging and at a higher rate in cirrhosis. The random defect pattern favors a stochastic process, e.g., free radical damage. However, the role of mutations of mtDNA remains to be established.
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PMID:Defects of the respiratory chain in the normal human liver and in cirrhosis during aging. 930 2

This study shows that the product of the hoxZ gene of Alcaligenes eutrophus H16 is a b-type cytochrome (cytochrome b(z)), which is essential for anchoring the membrane-bound hydrogenase (MBH) complex to the periplasmic side of the membrane and for H2-coupled respiration. The hoxZ product is not required for MBH translocation and H2-dependent reduction of the redox dye, 2,3,5-triphenyl-2-tetrazolium chloride. The lack of cytochrome b(z) does not affect the electron-transport activities linked to oxidation of succinate and NADH, although it enhances the electron-flow rate through the cytochrome-c oxidase pathway in hoxZdelta membranes. We show that the hoxZ product is a dihaem cytochrome b (haems with E(m7.0) of +10 mV and +166 mV) involved in H2-dependent electron transfer. We conclude that cytochrome b(z) of the A. eutrophus MBH complex is the link necessary for transfer of electrons from H2 to the ubiquinone pool and that it is required for attachment of MBH to the membrane.
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PMID:Functional and structural role of the cytochrome b subunit of the membrane-bound hydrogenase complex of Alcaligenes eutrophus H16. 931 Mar 76

Initial steps of the Azotobacter vinelandii respiratory chain have been studied on the inside-out subcellular vesicles. Two NADH:ubiquinone oxidoreductases were revealed: (i) proton-motive, capsaicin-sensitive and oxidizing dNADH as well as NADH enzyme and (ii) enzyme non-coupled to the energy conservation, capsaicin-resistant and oxidizing only NADH. The level of the oxidoreductases strongly depends upon [O2] and [NH3] in the growth medium. Increase in [O2] results in lowering of the coupled-enzyme level and in rise of the non-coupled one. Exclusion of NH3 from the growth medium increases the level of the non-coupled enzyme whereas that of the coupled enzyme remains constant. The O2-linked control of NADH:ubiquinone oxidoreductases requires CydR, a Fnr-like regulatory protein. Summarizing the above observations with those made in this group on the terminal steps of the A. vinelandii respiratory chains, one can assume that the respiratory protection of nitrogenase could be carried out by co-operation of the non-coupled NADH:ubiquinone oxidoreductase and the "partially coupled" quinoloxidase of the bd-type. Efficiency of this chain seems to be five-fold lower than that of the usual proton-motive chain (the coupled NADH:ubiquinone oxidoreductase, the Q-cycle and cytochrome oxidase of the o-type) which is also present in A. vinelandii and operates at low [O2].
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PMID:Two NADH:ubiquinone oxidoreductases of Azotobacter vinelandii and their role in the respiratory protection. 950 87

Our previous studies in iron-loaded rat heart cells showed that in vitro iron loading results in peroxidative injury, manifested in a marked decrease in rate and amplitude of heart cell contractility and rhythmicity, which is correctable by treatment with deferoxamine (DF). In the present studies we explored the role of mitochondrial damage in myocardial iron toxicity. Iron loading by 24-hour incubation with 0.36 mmol/L ferric ammonium citrate resulted in a decrease in the activity of nicotinamide adenine dinucleotide (NADH)-cytochrome c oxidoreductase (complex I+III) to 35.3%+/-11.2% of the value in untreated controls; of succinate-cytochrome c oxidoreductase (complex II+III) to 57.4%+/-3.1%; and of succinate dehydrogenase to 63.5%+/-12.6% (p < 0.001 in all cases). The decrease in activity of other mitochondrial enzymes, including NADH-ferricyanide reductase, succinate ubiquinone oxidoreductase (complex II), cytochrome c oxidase (complex IV), and ubiquinol cytochrome c oxidoreductase (complex III), was less impressive and ranged from 71.5%+/-15.8% to 91.5%+/-14.6% of controls. That the observed loss of respiratory enzyme activity was a specific effect of iron toxicity was clearly demonstrated by the complete restoration of enzyme activities by in vitro iron chelation therapy. Sequential treatment with iron and doxorubicin caused a loss of complex I+III and complex II+III activity that was greater than that seen with either agent alone but was only partially correctable by DF treatment. Alterations in cellular adenosine triphosphate measurements paralleled very closely the changes observed in respiratory complex activity. These findings demonstrate for the first time the impairment of cardiac mitochondrial respiratory enzyme activity caused by iron loading at conditions formerly shown to produce severe abnormalities in contractility and rhythmicity.
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PMID:Mitochondrial respiratory enzymes are a major target of iron toxicity in rat heart cells. 960 12


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