Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Peroxisomes were isolated from bovine and rat liver by use of differential and density gradient centrifugations. 2. In the final density gradient (Nycodenz) a distinct peak of ATPase activity codistributed with the peroxisome marker catalase and was well separated from the bulk of the ATPase activity and from markers for other subcellular organelles. 3. The peroxisome-associated ATPase had a pH optimum of 7.5 and was inhibited by N-ethylmaleimide, by N,N'-dicyclohexylcarbodiimide and by 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole, but was unaffected by up to 30 microM n-tributyltin chloride. 4. Prolonged incubation with oligomycin at high concentrations indicated that 50% of peroxisomal ATPase was resistant to this inhibitor. The oligomycin-sensitive ATPase activity required at least a four-fold higher ratio of inhibitor to protein for inhibition than mitochondrial ATPase did. It was concluded that oligomycin-sensitive and oligomycin-resistant ATPase may be associated with liver peroxisomes.
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PMID:Properties of ATPase activity associated with peroxisomes of rat and bovine liver. 183 59

The association of an ATPase with the yeast peroxisomal membrane was established by both biochemical and cytochemical procedures. Peroxisomes were purified from protoplast homogenates of the methanol-grown yeast Hansenula polymorpha by differential and sucrose gradient centrifugation. Biochemical analysis revealed that ATPase activity was associated with the peroxisomal peak fractions which were identified on the basis of alcohol oxidase and catalase activity. The properties of this ATPase closely resembled those of the mitochondrial ATPase of this yeast. The enzyme was Mg2+-dependent, had a pH optimum of approximately 8.5 and was sensitive to N,N'-dicyclohexylcarbodiimide (DCCD), oligomycin and azide, but not to vanadate. A major difference was the apparent Km for ATP which was 4-6 mM for the peroxisomal ATPase compared to 0.6-0.9 mM for the mitochondrial enzyme. Cytochemical experiments indicated that the peroxisomal ATPase was associated with the membranes surrounding these organelles. After incubations with CeCl3 and ATP specific reaction products were localized on the peroxisomal membrane, both when unfixed isolated peroxisomes or formaldehyde-fixed protoplasts were used. This staining was strictly ATP-dependent; in controls performed in the absence of substrate, in the presence of glycerol 2-phosphate instead of ATP, or in the presence of DCCD, staining was invariably absent. Similar staining patterns were observed in subcellular fractions and protoplasts of Candida utilis and Trichosporon cutaneum X4, grown in the presence of ethanol/ethylamine or ethylamine, respectively.
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PMID:A proton-translocating adenosine triphosphatase is associated with the peroxisomal membrane of yeasts. 288 51

Incubation of Trypanosoma cruzi mitochondrial ATPase (Fo-F1) with the xanthine oxidase system (XO), Fenton's reagent (Fe2+ + H2O2) and the ascorbate-Cu system, caused gradual loss of enzyme activity, which increased as a function of incubation time and rate of oxygen radical generation. The essential role of OH. radicals for ATPase inactivation was supported by a) the enzyme protection afforded by superoxide dismutase, catalase and mannitol, when using the XO system; b) the similar effect of mannitol and benzoate with Fenton's reagent; c) the similar effect of catalase, EDTA and histidine with the ascorbate-Cu system; d) the increased rate of ATPase inactivation by 1) the XO system supplemented with chelated iron, and 2) the ascorbate-Cu system supplemented with H2O2. Comparison of oxygen radical generators for their action on membrane-bound (Fo-F1) and soluble F1 revealed that ascorbate-Cu was the most effective one, possibly because of its capability of producing OH. radicals that react preferentially with the enzyme at their formation site.
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PMID:Inactivation of mitochondrial adenosine triphosphatase from Trypanosoma cruzi by oxygen radicals. 301 49

We studied a male newborn suffering from deficiency of ornithine transcarbamylase (OTC) that is due to a G-to-A substitution in codon 269 of the OTC gene. This study intends to define the cell biological mechanisms in this naturally occurring OTC mutation which may explain the mild clinical course in spite of the very low residual enzyme activity. Using immunogold labeling of thawed thin frozen sections of liver from this patient and a control liver, we analyzed the quantitative distribution of several mitochondrial proteins in the cytosol and the mitochondria of hepatocytes. In addition, the absolute volumes and surface densities of mitochondria and peroxisomes were determined. Our results show that the absolute volume of mitochondria in the patient's hepatocytes was increased to 141% (P < 0.001) without any change in the surface density indicating an increased number of mitochondria. In the patient's hepatocytes the peroxisomes were increased in size but not in number. The concentration of OTC was elevated in the cytosol (P < 0.001) and to a lesser extent in mitochondria (P < 0.01) of the patient's hepatocytes thus indicating a doubling of OTC relative to control liver cells. The quantity of OTC in mitochondria was 63% higher in diseased liver cells. By conventional thin section electron microscopy, mitochondria-like structures with poorly defined cristae and an electron-dense matrix were observed in the cytoplasm of the diseased hepatocytes. By immunoelectron microscopy, they contained the cytochrome c oxidase II subunit as well as DNA but lacked OTC, carbamylphosphate synthetase, F1-ATPase beta subunit and catalase. Thus it appears that these structures represent defective and probably degenerating mitochondria. Our data indicate that the reduced enzyme activity of the mutant OTC is partly compensated by an increased amount of enzyme molecules in the cytosol as well as mitochondria combined with an increase in the biogenesis of mitochondria.
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PMID:Ultrastructural, immunocytochemical and stereological investigation of hepatocytes in a patient with the mutation of the ornithine transcarbamylase gene. 764 31

Our previous work indicated that energy transduction, as measured by myocyte respiration, was inhibited by hydrogen peroxide, but the mitochondrial membrane potential was relatively unaffected. Therefore, we determined in the present study the critical steps in mitochondrial energy transduction by measuring the sensitivity to hydrogen peroxide of NADH-CoQ reductase, ATP synthase, and adenine nucleotide translocase in situ in myocytes. Adult rat heart cells were isolated using collagenase and incubated in the presence of 0.1-10 mM hydrogen peroxide for 30 min. Activities of NADH-CoQ reductase and oligomycin-sensitive ATP synthase were assayed enzymatically with sonicated myocytes, and adenine nucleotide translocase activities were determined by atractyloside-inhibitable [14C]ADP uptake of myocytes, permeabilized by saponin. The NADH-CoQ reductase and ATP synthase activities were inhibited to 77% and 67% of control, respectively, following an exposure to 10 mM hydrogen peroxide for 30 min. The adenine nucleotide translocase activities were inhibited in a concentration- and time-dependent manner and by 10 mM hydrogen peroxide to 44% of control. The dose-response relationship indicated that the translocase was the most susceptible to hydrogen peroxide among the three enzymes studied. Combined treatment of myocytes with 3-amino-1,2,4-triazole, 1,3-bis(2-chloroethyl)-1-nitrosourea and diethyl maleate (to inactivate catalase, to inhibit glutathione reductase activity, and to deplete glutathione, respectively) enhanced the sensitivity of translocase to hydrogen peroxide, supporting the view that the cellular defense mechanism is a significant factor in determining the toxicity of hydrogen peroxide. The results indicate that hydrogen peroxide can cause dysfunction in mitochondrial energy transduction, principally as the result of inhibition of adenine nucleotide translocase.
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PMID:Effects of hydrogen peroxide on mitochondrial enzyme function studied in situ in rat heart myocytes. 821 72

The storage of subunit c of mitochondrial ATP synthase, other hydrophobic peptides, and autofluorescent pigment in both late infantile (CLN2) and juvenile (CLN3) neuronal ceroid lipofuscinosis, but not in infantile (CLN1), has raised the question of abnormal mitochondrial function. We now report a partial deficiency in three types of fatty acid oxidation in intact skin fibroblasts from CLN2 and CLN3 patients, but not CLN1. We observed a statistically significant 33% reduction in palmitate (beta-oxidation; mainly mitochondrial) and lignocerate (beta-oxidation; mainly peroxisomal), and a 50% reduction in phytanic acid (alpha-oxidation; mainly peroxisomal) in the absence of exogenous carnitine. In contrast, when we measured fatty acid beta-oxidation (lignoceric acid and palmitic acid), in the same human skin fibroblasts, following lysis in the presence of carnitine, we found no difference in enzyme activity among normal, CLN1, CLN2, and CLN3. However, we did observe a 40% reduction in peroxisomal particulate (bound) catalase activity in CLN1 and CLN2 fibroblasts, which typically results from organellar lipid accumulation or a membrane abnormality. However, total catalase levels were normal, and Western blot analysis of this and three other major oxidant protective enzymes (Mn-dependent superoxide dismutase [MnSOD], CuZn-dependent superoxide dismutase [CuZnSOD], and glutathione peroxidase) were normal in CLN1, CLN2, and CLN3, as well as in liver from an animal (English Setter dog) model for CLN, which shows similar pathology and subunit c storage. Our data showing differences between CLN1 and forms CLN2 and CLN3 suggest some type of mitochondrial membrane abnormality as the source of the pathology in CLN2 and CLN3.
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PMID:Mitochondrial abnormalities in CLN2 and CLN3 forms of Batten disease. 897 98

In the present study we evaluated the effects of NO synthase (NOS) induction on the regulation of cytochrome c oxidase (CO) and F0F1-ATPase subunit expression in astroglial and mixed cortical cell cultures. In mixed cortical cell cultures, 18 h of treatment with lipopolysaccharide (LPS, 0.1 microgram/mL) plus interferon-gamma (INF-gamma, 10 U/mL) caused an increase of mRNAs for CO-I, F0F1-ATPase 6 and also for iNOS at 20 DIV. The induction of both CO-I and F0F1-ATPase 6 was abolished by the NOS inhibitor N-monomethyl-L-arginine (NMMA) or by the enzymatic scavenger superoxide dismutase/catalase (SOD/CAT). In primary astroglial cell cultures, treatment for 18 h with increasing concentrations of LPS and INF gamma, produced an increase in the amount of mitochondrial encoded CO-I and -II subunits, with no significant modifications of nuclear encoded subunit IV. An increase was also observed at level of transcription for CO-I and -II, and F0F1-ATPase 6 mRNAs. These effects were abolished by addition of NMMA or SOD/CAT. mRNA induction of CO-I was higher in mixed cortical than in astroglial cell cultures while that of F0F1-ATPase 6 was similar in both cell types. These results suggest that the expression of mitochondrial encoded subunits (CO-I, CO-II and F0F1-ATPase 6) is up-regulated in response to oxygen and NO reactive species. The activity of cytochrome c oxidase decreased after LPS/INF gamma treatment in both astroglial and mixed cortical cultures. The activity of ATP synthase was unmodified, while ATP content drastically decreased after LPS/INF gamma treatment, in both astroglial and mixed cortical cultures. The enzymatic activities of catalase and Mn-SOD (mitochondrial) showed a significant increase after LPS/INF gamma treatment, which was abolished by NMMA.
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PMID:Effect of nitric oxide synthase induction on the expression of mitochondrial respiratory chain enzyme subunits in mixed cortical and astroglial cell cultures. 989 46

It is not known why viable hepatocytes in fatty livers are vulnerable to necrosis, but associated mitochondrial alterations suggest that reactive oxygen species (ROS) production may be increased. Although the mechanisms for ROS-mediated lethality are not well understood, increased mitochondrial ROS generation often precedes cell death, and hence, might promote hepatocyte necrosis. The aim of this study is to determine if liver mitochondria from obese mice with fatty hepatocytes actually produce increased ROS. Secondary objectives are to identify potential mechanisms for ROS increases and to evaluate whether ROS increase uncoupling protein (UCP)-2, a mitochondrial protein that promotes ATP depletion and necrosis. Compared to mitochondria from normal livers, fatty liver mitochondria have a 50% reduction in cytochrome c content and produce superoxide anion at a greater rate. They also contain 25% more GSH and demonstrate 70% greater manganese superoxide dismutase activity and a 35% reduction in glutathione peroxidase activity. Mitochondrial generation of H(2)O(2) is increased by 200% and the activities of enzymes that detoxify H(2)O(2) in other cellular compartments are abnormal. Cytosolic glutathione peroxidase and catalase activities are 42 and 153% of control values, respectively. These changes in the production and detoxification of mitochondrial ROS are associated with a 300% increase in the mitochondrial content of UCP-2, although the content of beta-1 ATP synthase, a constitutive mitochondrial membrane protein, is unaffected. Supporting the possibility that mitochondrial ROS induce UCP-2 in fatty hepatocytes, a mitochondrial redox cycling agent that increases mitochondrial ROS production upregulates UCP-2 mRNAs in primary cultures of normal rat hepatocytes by 300%. Thus, ROS production is increased in fatty liver mitochondria. This may result from chronic apoptotic stress and provoke adaptations, including increases in UCP-2, that potentiate necrosis.
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PMID:Mitochondrial adaptations to obesity-related oxidant stress. 1086 May 43

Nitric oxide (NO) and its derivative, peroxynitrite (ONOO-), inhibit mitochondrial respiration, and this inhibition may contribute to both the physiological and cytotoxic actions of NO. Nanomolar concentrations of NO rapidly and reversibly inhibited cytochrome oxidase in competition with oxygen, as shown with isolated cytochrome oxidase, mitochondria, brain nerve terminals and cells. Cultured astrocytes and macrophages activated (by cytokines and endotoxin) to express the inducible form of NO synthase produced up to 1 microM NO, and inhibited their own respiration and that of co-incubated cells via reversible NO inhibition of cytochrome oxidase. NO-induced inhibition of respiration in brain nerve terminals resulted in rapid glutamate release, which might contribute to the neurotoxicity of NO. NO inhibition of cytochrome oxidase is reversible; however, incubation of cells with NO donors for 4 hours resulted in an inhibition of complex I, which was reversible by light and thiol reagents and may be due to nitrosylation of thiols in complex I. NO also caused the acute inhibition of catalase, stimulation of hydrogen peroxide production by mitochondria, and reaction with hydrogen peroxide on superoxide dismutase to produce peroxynitrite. Peroxynitrite inhibited complexes I, II and V (the ATP synthase), aconitase, creatine kinase, and increases the proton leak in isolated mitochondria. Peroxynitrite also caused opening of the permeability transition pore, resulting in the release of cytochrome c, which might then trigger apoptosis. Hypoxia/ischaemia also resulted in an acute reversible inhibition of cytochrome oxidase. Heart ischaemia caused the release of cytochrome c from mitochondria into the cytosol, and at the same time caspase-3-like-protease activity was activated in the cytoplasm. Addition of cytochrome c to non-ischaemic cytosol also caused activation of this protease activity, suggesting that caspase activation and consequent apoptosis is at least partly a result of this cytochrome c release.
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PMID:Nitric oxide, cytochrome c and mitochondria. 1098 53

Glucose depletion results in cellular stress and reactive oxygen species (ROS) production, which evokes adaptive and protective responses. One such protective response is the induction of haem oxygenase 1 (HO-1), which catalyses the rate-limiting step in haem degradation, liberating iron, CO and biliverdin. The present study evaluated the role of ROS and the mitochondrial electron-transport chain in the induction of HO-1 by glucose deprivation in HepG2 hepatoma cells. Either N-acetylcysteine, an antioxidant, or deferoxamine, an iron chelator, resulted in a dose-dependent inhibition of HO-1 mRNA and protein induction during glucose deprivation, suggesting a redox- and iron-dependent mechanism. Inhibitors of electron-transport chain complex III, antimycin A and myxothiazol, the ATP synthase inhibitor oligomycin and ATP depletion with 2-deoxyglucose or glucosamine also blocked HO-1 induction. To address the involvement of ROS further, specifically H(2)O(2), we showed that overexpression of catalase completely blocked HO-1 activation by glucose deprivation. In contrast, inhibition of nuclear factor kappa B, mitogen-activated protein kinase (MAPK), protein kinase A, protein kinase C, phosphoinositide 3-kinase, cyclo-oxygenase or cytosolic phospholipase A(2), did not prevent HO-1 induction. These results demonstrate that activation of the HO-1 gene by glucose deprivation is mediated by a 'glucose metabolic response' pathway via generation of ROS and that the pathway requires a functional electron-transport chain.
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PMID:Haem oxygenase 1 gene induction by glucose deprivation is mediated by reactive oxygen species via the mitochondrial electron-transport chain. 1258 63


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