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)

Age-related macular degeneration (AMD) is the leading cause of severe visual impairment in the elderly in developed countries. AMD patients have elevated levels of iron within the retinal pigment epithelia (RPE), which may lead to oxidative damage to mitochondria, disruption of retinal metabolism, and vision impairment or loss. As a possible model for iron-induced AMD, we investigated the effects of excess iron in cultured human fetal RPE cells on oxidant levels and mitochondrial cytochrome c oxidase (complex IV) function and tested for protection by N-tert-butyl hydroxylamine (NtBHA), a known mitochondrial antioxidant. RPE exposure to ferric ammonium citrate resulted in a time- and dose-dependent increase in intracellular iron, which increased oxidant production and decreased glutathione (GSH) levels and mitochondrial complex IV activity. NtBHA addition to iron-overloaded RPE cells led to a reduction of intracellular iron content, oxidative stress, and partial restoration of complex IV activity and GSH content. NtBHA might be useful in AMD due to its potential to reduce oxidative stress, mitochondrial damage, and age-related iron accumulation, which may damage normal RPE function and lead to loss of vision.
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PMID:N-tert-butyl hydroxylamine, a mitochondrial antioxidant, protects human retinal pigment epithelial cells from iron overload: relevance to macular degeneration. 1765 67

The present study elucidates a possible mechanism by which chronic organophosphate exposure (dichlorvos 6 mg/kg bw, s.c. for 12 weeks) causes neuronal degeneration. Mitochondria, as a primary site of cellular energy generation and oxygen consumption represent itself a likely target for organophosphate poisoning. Therefore, the objective of the current study was planned with an aim to investigate the effect of chronic dichlorvos exposure on mitochondrial calcium uptake, oxidative stress generation and its implication in the induction of neuronal apoptosis in rodent model. Mitochondrial preparation from dichlorvos (DDVP) treated rat brain demonstrated significant increase in mitochondrial Ca(2+) uptake (644.2 nmol/mg protein). Our results indicated decreased mitochondrial electron transfer activities of cytochrome oxidase (complex IV) along with altered mitochondrial complex I, and complex II activity, which might have resulted from elevated mitochondrial calcium uptake. The alterations in the mitochondrial calcium uptake and mitochondrial electron transfer enzyme activities in turn might have caused an increase in malondialdehyde, protein carbonyl and 8-hydroxydeoxyguanosine formation as a result of enhanced lipid peroxidation, and as well as protein and mtDNA oxidation. All this could have been because of enhanced oxidative stress, decreased GSH levels and also decreased Mn-SOD activity in the mitochondria isolated from dichlorvos treated rat brain. Thus, chronic organophosphate exposure has the potential to disrupt cellular antioxidant defense system which in turn triggers the release of cytochrome c from mitochondria to cytosol as well as caspase-3 activation in dichlorvos treated rat brain as revealed by immunoblotting experiments. Low-level long-term organophosphate exposure finally resulted in oligonucleosomal DNA fragmentation, a hallmark of apoptosis. These studies provide an evidence of impaired mitochondrial bioenergetics and apoptotic neuronal degeneration after chronic low-level exposure to dichlorvos.
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PMID:Impaired mitochondrial energy metabolism and neuronal apoptotic cell death after chronic dichlorvos (OP) exposure in rat brain. 1785 Aug 75

Proton pump inhibitors exert their preventive and healing effects on gastropathy induced by nonsteroidal anti-inflammatory drug (NSAIDs) by a dual action: the antisecretory and the antioxidant effect. The latter was investigated by using esomeprazole against indomethacin-induced gastric mucosa lesions in rats and assessed by a histomorphometric analysis. Treatment by intragastric gavage were 1% methocel as vehicle; esomeprazole 10, 30, or 60 micromol/kg; indomethacin 100 micromol/kg; and esomeprazole 10, 30, or 60 micromol/kg plus indomethacin 100 micromol/kg. The evaluation of glutathione (GSH) levels and respiratory chain complex activities [nicotinamide adenine dinucleotide, reduced (NADH)-ubiquinone oxidoreductase, succinate dehydrogenase, cytochrome C reductase, cytochrome oxidase] was performed in the isolated gastric mucosa. Esomeprazole (10-60 micromol/kg) dose dependently reversed, up to complete recovery, the inhibitory effect of indomethacin on GSH levels (approximately 60% inhibition) and mitochondrial enzyme activities (inhibition ranging from 60% to 75%). Indomethacin-induced mucosal injuries were reduced by esomeprazole. Thus, in addition to inhibiting acid secretion, the gastroprotective effect of esomeprazole can be ascribed to a reduction in gastric oxidative injury.
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PMID:Effects of esomeprazole on glutathione levels and mitochondrial oxidative phosphorylation in the gastric mucosa of rats treated with indomethacin. 1854 84

Sulfide oxidation in the lugworm, Arenicola marina (L.), is most likely localized in the mitochondria, which can either produce ATP with sulfide as a substrate or detoxify it via an alternative oxidase. The present study identified selective activators of the energy-conserving and the detoxifying sulfide oxidation pathways respectively. In the presence of the ROS scavengers glutathione (GSH) and ascorbate, isolated lugworm mitochondria rapidly oxidized up to 100 micromoll(-1) sulfide with maximal oxygen consumption rates but did not produce any ATP in the process. Under these conditions, salicylhydroxamic acid (SHAM), which is an inhibitor of the alternative oxidase of plant mitochondria, completely blocked oxygen consumption whereas inhibitors of complex III and IV had hardly any effect. By contrast, dehydroascorbate (DHA) enabled the mitochondria to gain ATP from sulfide oxidation even if the sulfide concentration far exceeded the threshold for inhibition of cytochrome oxidase. In the presence of dehydroascorbate, respiratory rates were independent of sulfide concentrations, with a respiratory control ratio of 2.1+/-0.2, and both oxygen consumption and ATP production were completely inhibited by myxothiazol and sodium azide but only marginally by SHAM. The present data indicate that a redox mechanism may contribute to the regulation of sulfide oxidation in lugworm mitochondria in vivo. Thus, mitochondria are presumably much more sulfide resistant in a cellular context than previously thought.
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PMID:Redox regulation of mitochondrial sulfide oxidation in the lugworm, Arenicola marina. 1868 15

Diallyl disulfide (DADS) and diallyl sulfide (DAS) are the major metabolites found in garlic oil and have been reported to lower cholesterol and prevent cancer. The molecular cytotoxic mechanisms of DADS and DAS have not been determined. The cytotoxic effectiveness of hydrogen versus allyl sulfides towards hepatocytes was found to be as follows: NaHS>DADS>DAS. Hepatocyte mitochondrial membrane potential was decreased and reactive oxygen species (ROS) and TBARS formation was increased by all three allyl sulfides. (1) DADS induced cytotoxicity was prevented by the H(2)S scavenger hydroxocobalamin, which also prevented cytochrome oxidase dependent mitochondrial respiration suggesting that H(2)S inhibition of cytochrome oxidase contributed to DADS hepatocyte cytotoxicity. (2) DAS cytotoxicity on the other hand was prevented by hydralazine, an acrolein trap. Hydralazine also prevented DAS induced GSH depletion, decreased mitochondrial membrane potential and increased ROS and TBARS formation. Chloral hydrate, the aldehyde dehydrogenase 2 inhibitor, however had the opposite effects, which could suggest that acrolein contributed to DAS hepatocyte cytotoxicity.
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PMID:The molecular mechanisms of diallyl disulfide and diallyl sulfide induced hepatocyte cytotoxicity. 1942 47

Mitochondria being the major source and target of reactive oxygen species (ROS) play a crucial role during ageing. We analyzed ageing and calorie restriction (CR)-induced changes in abundance of rat liver mitochondrial proteins to understand key aspects behind the age-retarding mechanism of CR. The combination of blue-native (BN) gel system with fluorescence Difference Gel Electrophoresis (DIGE) facilitated an efficient analysis of soluble and membrane proteins, existing as monomers or multi-protein assemblies. Changes in abundance of specific key subunits of respiratory chain complexes I, IV and V, critical for activity and/or assembly of the complexes were identified. CR lowered complex I assembly and complex IV activity, which is discussed as a molecular mechanism to minimize ROS production at mitochondria. Notably, the antioxidant system was found to be least affected. The GSH:GSSG couple could be depicted as a rapid mean to handle the fluctuations in ROS levels led by reversible metabolic shifts. We evaluated the relative significance of ROS generation against quenching. We also observed parallel and unidirectional changes as effect of ageing and CR, in subunits of ATP synthase, cytochrome P450 and glutathione S-transferase. This is the first report on such 'putatively hormetic' ageing-analogous effects of CR, besides the age-retarding ones.
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PMID:Modulation of oxidative phosphorylation machinery signifies a prime mode of anti-ageing mechanism of calorie restriction in male rat liver mitochondria. 1989 37

The present study suggests the importance of reactive oxygen species (ROS) and antioxidant metabolites as biochemical signals during the beneficial interactions of mitochondrial metabolism with photosynthetic carbon assimilation at saturating light and optimal CO2. Changes in steady-state photosynthesis of pea mesophyll protoplasts monitored in the presence of antimycin A [AA, inhibitor of cytochrome oxidase (COX) pathway] and salicylhydroxamic acid [SHAM, inhibitor of alternative oxidase (AOX) pathway] were correlated with total cellular ROS and its scavenging system. Along with superoxide dismutase (SOD) and catalase (CAT), responses of enzymatic components--ascorbate peroxidase (APX), monodehydroascorbate reductase (MDAR), glutathione reductase (GR) and non-enzymatic redox components of ascorbate-glutathione (Asc-GSH) cycle, which play a significant role in scavenging cellular ROS, were examined in the presence of mitochondrial inhibitors. Both AA and SHAM caused marked reduction in photosynthetic carbon assimilation with concomitant rise in total cellular ROS. Restriction of electron transport through COX or AOX pathway had differential effect on ROS generating (SOD), ROS scavenging (CAT and APX) and antioxidant (Asc and GSH) regenerating (MDAR and GR) enzymes. Further, restriction of mitochondrial electron transport decreased redox ratios of both Asc and GSH. However, while decrease in redox ratio of Asc was more prominent in the presence of SHAM in light compared with dark, decrease in redox ratio of GSH was similar in both dark and light. These results suggest that the maintenance of cellular ROS at optimal levels is a prerequisite to sustain high photosynthetic rates which in turn is regulated by respiratory capacities of COX and AOX pathways.
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PMID:Importance of ROS and antioxidant system during the beneficial interactions of mitochondrial metabolism with photosynthetic carbon assimilation. 1994 71

Mutations of mitochondrial DNA are associated with a wide spectrum of disorders, primarily affecting the central nervous system and muscle function. The specific consequences of mitochondrial DNA mutations for neuronal pathophysiology are not understood. In order to explore the impact of mitochondrial mutations on neuronal biochemistry and physiology, we have used fluorescence imaging techniques to examine changes in mitochondrial function in neurons differentiated from mouse embryonic stem-cell cybrids containing mitochondrial DNA polymorphic variants or mutations. Surprisingly, in neurons carrying a severe mutation in respiratory complex I (<10% residual complex I activity) the mitochondrial membrane potential was significantly increased, but collapsed in response to oligomycin, suggesting that the mitochondrial membrane potential was maintained by the F(1)F(o) ATPase operating in 'reverse' mode. In cells with a mutation in complex IV causing approximately 40% residual complex IV activity, the mitochondrial membrane potential was not significantly different from controls. The rate of generation of mitochondrial reactive oxygen species, measured using hydroethidium and signals from the mitochondrially targeted hydroethidine, was increased in neurons with both the complex I and complex IV mutations. Glutathione was depleted, suggesting significant oxidative stress in neurons with a complex I deficiency, but not in those with a complex IV defect. In the neurons with complex I deficiency but not the complex IV defect, neuronal death was increased and was attenuated by reactive oxygen species scavengers. Thus, in neurons with a severe mutation of complex I, the maintenance of a high potential by F(1)F(o) ATPase activity combined with an impaired respiratory chain causes oxidative stress which promotes cell death.
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PMID:Mechanism of neurodegeneration of neurons with mitochondrial DNA mutations. 2015 8

We have previously reported the occurrence of multiple forms of drug-metabolizing enzymes in camel tissues. Here, we investigate glutathione (GSH)-dependent redox homeostasis, reactive oxygen species (ROS) production and mitochondrial respiratory functions in camel tissues and compare them with imported domestic goats and laboratory rats and mice. Cytochrome P450 2E1 (CYP 2E1) and GSH-metabolizing enzymes were differentially expressed in the liver and kidney of these animals. Camel liver has significantly lower GSH pool than that in goats, rats and mice. Mitochondria isolated from the tissues of these animals showed a comparable ability to metabolize specific substrates for respiratory enzyme complexes I, II/III and IV. These complexes were metabolically more active in the kidney than in the liver of all the species. Furthermore, the activity of complex IV in camel tissues was significantly lower than in other species. On the other hand, complex II/III activity in camel kidney was higher compared to the other species. In addition, as expected, we observed that inhibitors of these enzyme complexes augment the production of mitochondrial ROS in camel and goat tissues. These results help to better understand the metabolic ability and adaptation in desert camels in comparison with domestic goats and laboratory rats and mice since they are exposed to different environmental and dietary conditions. Our study may also have implications in the pharmacology and toxicology of drugs and pollutants in these species.
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PMID:Redox homeostasis and respiratory metabolism in camels (Camelus dromedaries): comparisons with domestic goats and laboratory rats and mice. 2053 92

The responses of various cell functional parameters to potassium cyanide (KCN) were investigated in isolated rat hepatocytes to examine their quantitative and temporal relationship to inhibition of mitochondrial respiration. Both cultures and suspensions of hepatocytes, maintained in hormone-supplemented culture medium at 37 degrees C under an air: CO(2) (95:5) atmosphere, were used in these studies. The earliest and most sensitive change detected was inhibition of O(2) consumption (EC (50) = 78 mu m ); other early changes included depression in ATP and ATP/ADP, inhibition of urea synthesis, and elevation in lactate/pyruvate. The effect on ATP depression at 10 min was reversed by replacement with fresh medium containing no cyanide (t (1 2 )=9 min ). Increased release of lactate dehydrogenase and acid phosphatase occurred much later during the incubation (120 or 240 min) and at much higher KCN concentrations (>/=0.5 mm) than the other changes. These observations are consistent with inhibition of mitochondrial respiration being the initiating or major contributing factor in cyanide-induced cytotoxicity in hepatocytes, but because of the difference in EC(50) values for depression of O(2) consumption and energy-dependent parameters and for intracellular enzyme release, other mechanisms may also contribute to cell death. Reduced glutathione content and lipid peroxidation in the cells, assessed by measuring thiobarbituric acid reactants, were not significantly changed, and the mechanism leading up to cell death remains uncharacterized. The cyanide concentrations in vitro that produced inhibition of O(2) consumption were in the same range as those in blood and liver that inhibited cytochrome oxidase in vivo at lethality. The results in the hepatocyte model, therefore, can explain why the liver is not a target organ in massive, acute cyanide poisoning, in that overt signs develop at higher concentrations and after longer times than are applicable for the death of the animal.
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PMID:Cyanide-induced cytotoxicity to isolated hepatocytes. 2070 82


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