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 membrane-anchored thioredoxin-like protein (TlpA) from the Gram-negative soil bacterium Bradyrhizobium japonicum was initially discovered due to its essential role in the maturation of cytochrome aa3. A soluble form of TlpA lacking the N-terminal membrane anchor acts as a protein thiol:disulfide oxidoreductase. TlpA possesses an active-site disulfide bond common to all members of the thiol:disulfide oxidoreductase family. In addition, it contains two non-active-site cysteines that form a structural disulfide bond (Loferer, H., Bott, M., and Hennecke, H. (1993) EMBO J. 12, 3373-3383; Loferer, H., and Hennecke, H. (1994) Eur. J. Biochem. 223, 339-344). Here, we compare the far- and near-UV CD spectra of TlpA before and after reduction of both disulfides by dithiothreitol and show that the non-active-site disulfide bond is not required for the integrity of TlpA's native conformation. In contrast to dithiothreitol, reduced glutathione (GSH) selectively reduces the active-site disulfide and leaves the non-active-site disulfide bond intact, even at high molar excess over TlpA. The selective reduction of the active-site disulfide bond leads to a 10-fold increase of the intrinsic tryptophan fluorescence of TlpA at 355 nm, which may be interpreted as a quenching of tryptophan fluorescence by the active-site disulfide bond. Using the specific fluorescence of TlpA as a measure of its redox state, a value of 1.9 +/- 0.2 M was determined for the TlpA:glutathione equilibrium constant at pH 7.0, demonstrating that TlpA is a reductant, like cytoplasmic thioredoxins. The DsbA protein, which acts as the final oxidant of periplasmic secretory proteins in Escherichia coli, is not capable of oxidizing the active-site cysteines of TlpA. This suggests that TlpA's primary role in vivo is keeping the thiols of certain proteins reduced and that TlpA's active, reduced state may be maintained owing to its kinetically restricted oxidation by other periplasmic disulfide oxidoreductases such as DsbA.
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PMID:A bacterial thioredoxin-like protein that is exposed to the periplasm has redox properties comparable with those of cytoplasmic thioredoxins. 759 22

Lipid peroxidation and antioxidative mechanisms were investigated in liver mitochondria from bile duct ligated rats (BDL rats) and correlated with the activity of enzyme complexes of the electron transport chain. In comparison to pair-fed control rats, BDL rats had increased concentrations of thiobarbituric acid reacting substances (TBARS) per gram of liver and per milligram of mitochondrial protein 3, 7, 14, and 28 days after surgery. The hepatic glutathione (GSH) content was decreased in BDL rats 28 days after surgery when expressed per gram of liver but equal between BDL and control rats when expressed per liver. The mitochondrial GSH content was decreased in BDL rats by 20% to 33% from day 7 after surgery. The concentrations of ubiquinone-9 and ubiquinone-10, substances involved in electron transport and efficient antioxidants, were both decreased in BDL rats 14 and 28 days after surgery per gram of liver and per milligram of mitochondrial protein. When expressed per liver, ubiquinone-9 was decreased in BDL rats from day 7 after surgery. In comparison with controls, the decrease in total mitochondrial ubiquinone content in BDL rats averaged 52% 14 days and 38% 28 days after surgery. The activity of the succinate:ferricytochrome c oxidoreductase (complexes II and III of the electron transport chain) was decreased in BDL rats at days 7, 14, and 28 after surgery, and the activity of the ferrocytochrome c:oxygen oxidoreductase (complex IV) was reduced at 14 and 28 days after surgery. The mitochondrial concentration of TBARS showed a negative and the concentrations of GSH and ubiquinone a positive correlation with the activity of the succinate:ferricytochrome c oxidoreductase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reduced antioxidative capacity in liver mitochondria from bile duct ligated rats. 763 30

Studies from our laboratory have shown that short-term ethanol exposure inhibits epidermal growth factor-dependent replication of cultured fetal rat hepatocytes, along with a drop in ATP level, and that these effects could be caused, at least in part, by ethanol-induced oxidative stress. In these prior studies, mitochondrial morphology was abnormal and membrane lipid peroxidation products were increased, along with reduced transmembrane potential and enhanced permeability to sucrose. To define the effects of ethanol on mitochondrial function further, the present study examines the impact of ethanol exposure on mitochondrial electron transport chain components. A 24-hr exposure of cultured fetal rat hepatocytes to ethanol (2.5 mg/ml) reduced mitochondrial complex I activity by 16% (p < 0.05), complex IV by 28% (p < 0.05), and succinate dehydrogenase by 23% (p < 0.05). This reduction was paralleled by lower ADP translocase activity (24%, p < 0.05) and diminished mitochondrial glutathione (GSH) (20%, p < 0.05). Pretreatment with 0.1 mM S-adenosyl methionine, before ethanol exposure, normalized mitochondrial GSH along with activities of complex I, complex IV, and succinate dehydrogenase. A 3-hr exposure of isolated mitochondria (which do not metabolize ethanol) to ethanol (2.5 mg/ml), inhibited the activities of complex I (19%, p < 0.05), complex IV (24%, p < 0.05), and of ATP synthesis (20%, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of acute ethanol exposure on cultured fetal rat hepatocytes: relation to mitochondrial function. 769 41

The effect of depletion of reduced glutathione (GSH) on brain mitochondrial function and N-acetyl aspartate concentration has been investigated. Using pre-weanling rats, GSH was depleted by L-buthionine sulfoximine administration for up to 10 days. In both whole brain homogenates and purified mitochondrial preparations complex IV (cytochrome c oxidase) activity was decreased, by up to 27%, as a result of this treatment. In addition, after 10 days of GSH depletion, citrate synthase activity was significantly reduced, by 18%, in the purified mitochondrial preparations, but not in whole brain homogenates, suggesting increased leakiness of the mitochondrial membrane. The whole brain N-acetyl aspartate concentration was also significantly depleted at this time point, by 11%. It is concluded that brain GSH is important for the maintenance of optimum mitochondrial function and that prolonged depletion leads also to loss of neuronal integrity. The relevance of these findings to Parkinson's disease and the inborn errors of glutathione metabolism are also discussed.
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PMID:Depletion of brain glutathione is accompanied by impaired mitochondrial function and decreased N-acetyl aspartate concentration. 773 56

Carbohydrate restriction and caloric restriction (60% restriction of calories in relation to controls in both cases) were imposed on OF1 mice during 8 weeks in their growing phase. The three groups of animals ingested the same amount of vitamins and minerals. Kidney ascorbate strongly decreased in both restriction groups. Nevertheless, global caloric restriction significantly increased kidney antioxidant glutathione (GSH)/oxidized glutathione (GSSG) ratio, a sign of a reduced kidney oxidative stress. Increased glutathione peroxidase and cytochrome oxidase activities and decreased in vivo peroxidation were found in the kidney when the restriction was performed by substituting carbohydrates by nonnutritive bulk. No significant changes were observed for superoxide dismutase, catalase, glutathione reductase, glutathione, uric acid, malondialdehyde (HPLC), or in vitro sensitivity to peroxidation in the kidney. The results, reported for the first time in this tissue, show that short-term caloric restriction can increase the capacity for enzymatic decomposition of hydroperoxides and can decrease oxidative stress in the kidney, thus suggesting a role for free radical metabolism in the caloric restriction phenomenon.
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PMID:Caloric and carbohydrate restriction in the kidney: effects on free radical metabolism. 818 43

Growing OF1 mice were treated on a short-term basis with ad libitum, caloric-restricted, or carbohydrate-restricted diets, maintaining the same intake of vitamins and minerals in the three groups. Caloric intake was 60% of controls both in the caloric-restricted and in the carbohydrate-restricted groups. Neither global nor carbohydrate restriction changed liver superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, cytochrome oxidase, GSH, uric acid, or malondialdehyde (HPLC). Ascorbate was decreased in both restricted groups. Carbohydrate restriction, but not caloric restriction, increased unsaturation indexes of fatty acids in all lipid classes analyzed and increased sensitivity to peroxidation by one order of magnitude. It is concluded that short-term caloric restriction does not seem to increase antioxidants and decrease peroxidation in the mouse liver whereas long-term restriction can avoid decreases of antioxidants and increases of peroxidation during aging. Our experiments support the prevailing view that the caloric restriction phenomenon is due to a reduction in calories themselves instead of to a reduction in carbohydrates. This last manipulation strongly increases sensitivity to peroxidative damage in the liver. The results show that in vivo fatty acid unsaturation is a main factor in determining the sensitivity to lipid peroxidation.
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PMID:Relationship between lipid peroxidation, fatty acid composition, and ascorbic acid in the liver during carbohydrate and caloric restriction in mice. 821 21

Previous studies have shown that the increase of the enzymatic antioxidant defense that takes place in the fetal rat lung at the end of gestation can be accelerated by the synthetic glucocorticoid dexamethasone and diminished by metyrapone, a blocker of glucocorticoid synthesis. Since it is known that the fetal adrenal does not start to synthesize corticosterone until the last 20% of gestation, pregnant rats were bilaterally adrenalectomized on the first day of gestation in order to clarify the role of the endogenous maternal hormone on the development of the enzymatic and nonenzymatic antioxidant systems of fetal lung. This early adrenalectomy did not change fetal lung catalase, glutathione peroxidase, glutathione reductase, cytochrome oxidase, GSH, ascorbate, and uric acid at term. The presence of the maternal glands is not essential for lung antioxidant development in the fetus and that the stimulus of fetal corticosterone during the last 20% of gestation is enough to achieve a normal maturation of the fetal lung enzymatic and nonenzymatic antioxidant systems.
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PMID:Effect of early maternal adrenalectomy on antioxidant enzymes, GSH, ascorbate, and uric acid in the rat fetal lung at term. 825 57

Morphological and biochemical changes in mitochondrial have been reported early in the course of cocaine-induced hepatotoxicity. This study was designed to examine the effects of repeated cocaine exposure in vivo on mitochondrial respiration, activities of respiratory chain enzymes, and lipid peroxide measures in liver. Male Sprague-Dawley rats were exposed to cocaine (5 i.p. injections of 25 mg/kg; 3-day period). Blood and liver samples were taken, and hepatic mitochondria were isolated by differential centrifugation. The cocaine-treated rats developed oxidative stress in hepatic mitochondria as evidenced by a significant increase in malonaldialdehyde (MDA; 52%; p < 0.0001) and a decreased glutathione (GSH; 22%; p < 0.0003). Blood aspartate aminotransferase (AST) and glutathione s-transferase (GST) levels in cocaine groups were significantly elevated (2.6 and 3.2 fold, respectively; p < 0.0001 for both). Cocaine caused a decrease in state-3 respiration and respiratory control ratio (RCR) ratio when exposed to site I and II substrates; these changes were parallelled by a decrease in complex I (22%; p < 0.003), succinate cytochrome c reductase (27%; p < 0.004), and complex IV (24%; p < 0.003). In conclusion, functional abnormalities of hepatic mitochondria accompany lipid peroxidation caused by cocaine, supporting the hypothesis that the mitochondria is one of the major intracellular targets of cocaine hepatotoxicity.
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PMID:Impairment of mitochondrial respiration and electron transport chain enzymes during cocaine-induced hepatic injury. 907 24

Ceramide is a sphingolipid that is generated in the signaling of inflammatory cytokines such as tumor necrosis factor (TNF), which exerts many functional roles depending on the cell type where it is produced. Since TNF cytotoxicity is mediated by overproduction of reactive oxygen species from mitochondria, we have examined the role of ceramide in generation of oxidative stress in isolated rat liver mitochondria. The present studies demonstrate that addition of N-acetylsphingosine (C2-ceramide) to mitochondria led to an increase of fluorescence of dihydrorhodamine 123 or dichlorofluorescein-stained mitochondria, indicating formation of hydrogen peroxide. Such effect was significant at 0.25 microM and maximal at 1-5 microM C2, decreasing at greater concentrations. This inductive effect of ceramide was mimicked by N-hexanoylsphingosine at the same concentration range, whereas the immediate precursor of C2, C2-dihydroceramide increased hydrogen peroxide at 1-5 microM. Sphingosine generated hydrogen peroxide at concentrations >/=10 microM, whereas diacylglycerol failed to increase hydrogen peroxide. The increase in hydrogen peroxide induced by C2 was not triggered by mitochondrial permeability transition as C2 did not induce mitochondrial swelling. Blocking electron transport chain at complex I and II prevented the increase in hydrogen peroxide induced by C2; however, interruption of electron flow at complex III by antimycin A potentiated the inductive effect of C2. Depletion of matrix GSH prior to exposure to ceramide resulted in a potentiated increase (2-fold) of hydrogen peroxide generation, leading to lipid peroxidation and loss of activity of respiratory chain complex IV compared with GSH-repleted mitochondria. Mitochondria isolated from TNF-treated cells showed an increase (2-3-fold) in the amount of ceramide compared with mitochondria from untreated cells. These results suggest that mitochondria are a target of ceramide produced in the signaling of TNF whose effect on mitochondrial electron transport chain leads to overproduction of hydrogen peroxide and consequently this phenomena may account for the generation of reactive oxygen species during TNF cytotoxicity.
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PMID:Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. 911 Oct 45

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


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