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 present study investigates the influence of energy related metabolic stress on amyloid precursor protein (APP) non-amyloidogenic secretory processing in COS cells. The effect of glucose deprivation on soluble APP (sAPP) secretion has been evaluated: incubation of COS cells with 50 mM 2-deoxy-D-glucose (2-DG) in glucose free medium was able to reduce sAPP secretion (-26%). Sodium azide (NaN3), an inhibitor of cytochrome c oxidase (complex IV of the mitochondrial electron transfer chain) decreased sAPP release in a concentration dependent way (maximum -75%). Treatment of COS cells with the antioxidant glutathione (GSH) fully antagonized the inhibitory effect of azide (1 mM) and elicited sAPP release over basal level. These results suggest that the inhibition of energy metabolism can influence APP processing leading to a decreased secretion of non-amyloidogenic fragments of APP.
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PMID:Effect of energy shortage and oxidative stress on amyloid precursor protein metabolism in COS cells. 929 Nov 53

We investigated the effect of glutathione (GSH) depletion on mitochondrial function and generation of reactive oxygen intermediates (ROI) in PC12 cells in vitro. Direct depletion of cellular GSH using ethacrynic acid (EA, 500 mM) resulted in a concentration-dependent generation of ROI and cell death within 24 h. Treatment with 500 microM L-buthionine sulfoximine (BSO), which inhibits GSH synthesis, reduced cellular GSH but did not lead to generation of ROI. Furthermore, cells remained viable up to 72 h. Analysis of subcellular fractions revealed complete loss of cytosolic and mitochondrial GSH within 4 h of EA treatment. In contrast, BSO-treated cells still maintained 100% GSH in the mitochondrial fraction for 4 h and 6% for 48 h. Mitochondrial complex II/IIi and IV activities were not significantly decreased up to 48 h of BSO treatment while EA treatment resulted in a complete loss of complex II/III activity and a 70% reduction of complex IV activity within 4 h. These findings suggest that mitochondrial GSH is critical for the maintenance of mitochondrial function and cellular viability.
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PMID:Differential effects of L-buthionine sulfoximine and ethacrynic acid on glutathione levels and mitochondrial function in PC12 cells. 1031 99

Bilirubin is a well-known neurotoxin and presents a particular problem in newborn infants. This is partly due to the high incidence of unconjugated hyperbilirubinemia in that age group, but may also be due to increased vulnerability to bilirubin toxicity. The brain may be able to protect itself against bilirubin toxicity through a process of oxidation. The responsible enzyme is localized on the inner mitochondrial membrane and appears to be more active in glia than in neurons and to increase in activity with postnatal maturation. Here we have investigated the possibility that the responsible enzyme might be a cytochrome oxidase, malate dehydrogenase, or monoamine oxidase, all enzymes located on the inner mitochondrial membrane. Mitochondria were obtained from rat brains through homogenization and differential centrifugation in sucrose medium. The ability of mitochondrial membranes to oxidize bilirubin was measured by following the change in optical density at 440 nm of a bilirubin solution to which a membrane suspension had been added. The activity was not changed by in vitro inhibitors of malate dehydrogenase or monoamine oxidase, but was moderately inhibited by ketoconazole and clotrimazole, both known inhibitors of hepatic cytochrome P450 oxidases. Activity was inhibited by depletion of cytochrome c in the mitochondria and reconstituted by reintroducing cytochrome c into the reaction mixture. The reaction was not modified by the addition of a free radical quencher, but was inhibited by removal of oxygen from the reaction mixture. The activity was significantly inhibited by cyanide. Activity was retained in a 100,000-g pellet and was not influenced by the addition of NAD, NADP, NADH, NADPH, GSH, or GSSH to this pellet. We conclude that the bilirubin-oxidizing activity in brain mitochondrial membranes is cytochrome c dependent, but does not appear to be unequivocally identifiable as a cytochrome P450 oxidase.
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PMID:Oxidation of bilirubin in the brain-further characterization of a potentially protective mechanism. 1056 68

Biological systems that produce or are exposed to nitric oxide (NO radical) exhibit changes in the rate of oxygen free radical production. Considering that mitochondria are the main intracellular source of oxygen radicals, and based on the recently documented production of NO(radical) by intact mitochondria, we investigated whether NO(radical), produced by the mitochondrial nitric-oxide synthase, could affect the generation of oxygen radicals. Toward this end, changes in H(2)O(2) production by rat liver mitochondria were monitored at different rates of endogenous NO(radical) production. The observed changes in H(2)O(2) production indicated that NO(radical) affected the rate of oxygen radical production by modulating the rate of O(2) consumption at the cytochrome oxidase level. This mechanism was supported by these three experimental proofs: 1) the reciprocal correlation between H(2)O(2) production and respiratory rates under different conditions of NO(radical) production; 2) the pattern of oxidized/reduced carriers in the presence of NO(radical), which pointed to cytochrome oxidase as the crossover point; and 3) the reversibility of these effects, evidenced in the presence of oxymyoglobin, which excluded a significant role for other NO(radical)-derived species such as peroxynitrite. Other sources of H(2)O(2) investigated, such as the aerobic formation of nitrosoglutathione and the GSH-mediated decay of nitrosoglutathione, were found quantitatively negligible compared with the total rate of H(2)O(2) production.
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PMID:The modulation of oxygen radical production by nitric oxide in mitochondria. 1110 47

Rats fed a vitamin E-depleted diet for 48 weeks had undetectable levels of vitamin E in the gastrocnemius muscle and liver, leading to elevated malondialdehyde levels in both tissues and an elevated GSH level in muscle. Skeletal-muscle mitochondria showed decreased mitochondrial respiratory chain (MRC) activities, whereas liver MRC activities were increased. Exposure of normal rat liver submitochondrial particles (SMPs) to an in vitro NADPH-dependent lipid peroxidation system resulted in a dose-dependent increase in lipid peroxidation and inhibition of complex I and complex IV activities. Complex I exhibited greater sensitivity to lipid peroxidation than complex IV. At low and high NADPH concentrations, the rate of lipid peroxidation and the level of enzyme inhibition were essentially the same in liver SMPs from both vitamin E-deficient and control rats, suggesting that under these conditions, the loss of vitamin E did not exacerbate the effects of either lipid peroxidation or enzyme inhibition. These results indicate that normal vitamin E levels in liver mitochondria are not required for protection against lipid peroxidation and are consistent with the normal liver mitochondrial function in vitamin E-deficient animals. This suggests other antioxidants, such as ubiquinol and GSH, may be more important in protecting liver mitochondria and MRC from lipid peroxidation.
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PMID:Sensitivity of respiratory chain activities to lipid peroxidation: effect of vitamin E deficiency. 1146 62

The toxicity of most drugs is associated with their enzymatic conversion to toxic metabolites. Bioactivation reactions occur in a range of cellular organs and organelles, including mitochondria. We have investigated different effects (i.e. growth inhibition, mortality and genotoxicity) of doxorubicin, epirubicin and mitoxantrone on the D7 strain of Saccharomyces cerevisiae and on its petite (rho degrees ) respiratory-deficient mutant at various cellular concentrations of cytochrome P450 and glutathione (GSH). The data confirmed the importance of oxygen production for doxorubicin toxicity. The complete absence, or a very low level, of cytochrome oxidase subunit IV conferred some resistance to doxorubicin. Low GSH levels decreased resistance to doxorubicin in both strains, suggesting that thiol depletion could potentiate membrane lipid peroxidation. Doxorubicin induction of petite colonies suggests that the drug is able to select rather than induce respiratory-deficient mutants. Epirubicin induced levels of cytotoxicity similar to those of doxorubicin. The effects did not appear to be significantly dependent on mitochondrial function or GSH levels, whereas cells were strongly protected by cytochrome P450. GSH did not induce an evident alteration. Neither were genotoxic effects induced. Mitoxantrone had reduced levels of both growth inhibition and cytotoxicity in comparison to anthracyclines and induced convertants, revertants and aberrants. All the effects considered were amplified at high cytochrome P450 cellular concentrations, although the drug was also shown to act without previous metabolism via cytochrome P450. Anthracenedione effectiveness was increased by metabolism via cytochrome P450 and partially reduced by GSH. However, further mechanisms were suggested, which might implicate mitochondrial function and/or production of electrophilic cytotoxic and/or genotoxic intermediates by means of GSH conjugation. The biological effectiveness of doxorubicin, epirubicin and mitoxantrone on S.cerevisiae was shown to be strictly dependent on cell-specific physiological/biochemical conditions, such as a functional respiratory chain and levels of cytochrome P450 and GSH.
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PMID:Saccharomyces cerevisiae as an eukaryotic cell model to assess cytotoxicity and genotoxicity of three anticancer anthraquinones. 1247 32

Fluorescence microscopy of A549 cells stained with a glutathione (L-gamma-glutamyl-L-cysteinylglycine, GSH)-specific polyclonal antibody displayed uniform staining of the peri-nuclear cytosol, with the nuclear region apparently lacking GSH staining. This discontinuous staining was confirmed in other cell types and also corroborated in A549 cells stained with the thiol-reactive dye mercury orange. The selectivity of antibody binding was confirmed by buthionine sulfoximine (BSO)-dependent inhibition of GSH synthesis. However, confocal visualization of antibody-stained A549 cells in the z-plane revealed the majority of the peri-nuclear staining intensity in the upper half of the cell to be associated with mitochondria, as confirmed by double staining for cytochrome oxidase. Integration of the confocal signals from the nuclear and cytosolic regions halfway down the z-plane showed that the GSH concentrations of these compartments are close to equilibrium. Confirmation of the relatively high levels of mitochondrial glutathione was provided in cells treated with BSO and visualized in z-section, revealing the mitochondrial GSH content of these cells to be well preserved in apposition to near-complete depletion of cytosolic/nuclear GSH. Localized gradients within the cytosolic compartment were also visible, particularly in the z-plane. The antibody also provided initial visualization of the compartmentalization of protein-GSH mixed disulfides formed in A549 cells exposed to diamide. Discontinuous staining was again evident, with heavy staining in membrane blebs and in the nuclear region. Using FACS analysis of anti-GSH antibody-stained Jurkat T lymphocytes, we also demonstrated population variations in the cellular compliment of GSH and protein-GSH mixed disulfides, formed in response to diamide. In addition, we showed cell-cycle variation in GSH content of the cells, with the highest levels of GSH associated with the G2/M mitotic phase of the cell cycle, using double staining with propidium iodide. Similar FACS analyses performed in isolated mitochondria presented a considerable variation in GSH content within mitochondria of uniform granularity from the same preparation.
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PMID:Visualization of the compartmentalization of glutathione and protein-glutathione mixed disulfides in cultured cells. 1247 11

Ethinyl estradiol (EE) is a strong promoter and weak hepatocarcinogen in rats. Previously, we demonstrated that EE enhanced the transcript levels of nuclear genome- and mitochondrial genome-encoded genes and respiratory chain activity in female rat liver, and also inhibited transforming growth factor beta (TGFbeta)-induced apoptosis in cultured liver slices and hepatocytes from female rats. In this study, using cultured female rat hepatocytes, we observed that EE, within 24 h, increased the transcript levels of the mitochondrial genome-encoded genes cytochrome oxidase subunits I, II, and III. This effect was accompanied by increased mitochondrial respiratory chain activity, as reflected by increased mitochondrial superoxide generation, and detected by lucigenin-derived chemiluminescence and cellular ATP levels. EE also enhanced the levels of Bcl-2 protein. Biochemical analyses indicated that EE significantly increased both the levels of glutathione (reduced [GSH] and oxidized [GSSG] forms) per mg protein in mitochondria and nuclei, while the percentage of total glutathione in the oxidized form was not affected. This finding was supported by confocal microscopy. These effects caused by EE may contribute, at least in part, to the EE-mediated inhibition of hepatic apoptosis.
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PMID:Enhanced mitochondrial gene transcript, ATP, bcl-2 protein levels, and altered glutathione distribution in ethinyl estradiol-treated cultured female rat hepatocytes. 1285 39

Oxidized lipids are capable of initiating diverse cellular responses through both receptor-mediated mechanisms and direct posttranslational modification of proteins. Typically, exposure of cells to low concentrations of oxidized lipids induces cytoprotective pathways, whereas high concentrations result in apoptosis. Interestingly, mitochondria can contribute to processes that result in either cytoprotection or cell death. The role of antioxidant defenses such as glutathione in adaptation to stress has been established, but the potential interaction with mitochondrial function is unknown and is examined in this article. Human umbilical vein endothelial cells (HUVEC) were exposed to oxidized LDL (oxLDL) or the electrophilic cyclopentenone 15-deoxy-Delta 12,14-PGJ2 (15d-PGJ2). We demonstrate that complex I activity, but not citrate synthase or cytochrome-c oxidase, is significantly induced by oxLDL and 15d-PGJ2. The mechanism is not clear at present but is independent of the induction of GSH, peroxisome proliferator-activated receptor (PPAR)-gamma, and PPAR-alpha. This response is dependent on the induction of oxidative stress in the cells because it can be prevented by nitric oxide, probucol, and the SOD mimetic manganese(III) tetrakis(4-benzoic acid) porphyrin chloride. This increased complex I activity appears to contribute to protection against apoptosis induced by 4-hydroxynonenal.
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PMID:Oxidized low-density lipoprotein and 15-deoxy-delta 12,14-PGJ2 increase mitochondrial complex I activity in endothelial cells. 1288 Dec 7

A phenolic antioxidant 3-tert-butyl-4-hydroxyanisole (BHA) is a widely used food additive. BHA had cytotoxicity in human monocytic leukemia U937 cells. BHA at 0.75 mM caused nuclear condensation and fragmentation, structural damage in mitochondria, decrease in mitochondrial transmembrane potential, and internucleosomal DNA cleavage. It induced the activities of caspase-3 and/or -7, -6, -8 and -9, especially high when DEVD-MCA was the substrate (caspase-3 and/or -7). DEVDase activity increased in time- and dose-dependent manner and high activity was observed in lysates of cells treated for 3 h at 0.75 mM. Addition of GSH (reduced glutathione) during the treatment of cells with BHA inhibited the induction of DEVDase activity, and the intracellular GSH level decreased as the concentration of BHA was raised. Intracellular ATP levels decreased in time- and dose-dependent manner when the cells were treated with BHA in the presence or absence of glucose. Enzyme activities involved in the respiratory chain were assayed with the mitochondrial fraction prepared from U937 cells. BHA distinctly inhibited NADH-ubiquinone oxidoreductase (complex I) and cytochrome c oxidase (complex IV) at low concentrations. Succinate-ubiquinone oxidoreductase (complex II) was also inhibited, but to somewhat less extent. Without mitochondrial enzymes, BHA stimulated the ubiquinol-dependent reduction of cytochrome c (complex III), but it might have some detrimental effects on the mitochondrial enzyme reaction of complex III. The inhibition of mitochondrial oxidative phosphorylation might corroborate the mechanistic evidence for apoptosis of leukemia cells by BHA. Cell death induced by BHA is primarily ascribable to apoptosis.
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PMID:Molecular mechanism of cell death induced by the antioxidant tert-butylhydroxyanisole in human monocytic leukemia U937 cells. 1499 91


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