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:2.3.3.1 (citrate synthase)
4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The postnatal development of the complexes of the electron transport chain in isolated rat brain mitochondria were investigated. Nonsynaptosomal brain mitochondria were isolated from rats aged 1-60 days, and the activities of mitochondrial complexes I, II-III, IV, V and citrate synthase were measured. There was a significant increase in the activity of complex I from postnatal day 1 to day 21, and in the activities of complex II-III, complex IV and citrate synthase from postnatal day 1 to day 60. In contrast, the activity of complex V increased significantly between postnatal day 1 and day 10 where it attained adult levels. These data are consistent with the increasing demand for mitochondrial ATP production as the brain develops and as aerobic glycolysis becomes the major pathway for energy production.
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PMID:Postnatal development of the complexes of the electron transport chain in isolated rat brain mitochondria. 776 12

The expression of both mitochondrial and nuclear genes encoding enzymes involved in electron transport and oxidative phosphorylation was examined in bovine cardiac tissue during early growth, development and aging. The steady state level of mRNAs for mitochondrial genes including ATPase 6. COXII and cyt b increased 2.5-4-fold relative to early fetal levels in late fetal and young adult tissues and showed a marked decline (30-50%) in older adult tissues. Similar results were found with the nuclear genes, COXVB and ATP-beta synthase showing coordinate regulation of the two genomes. An increase in mtDNA copy number correlated with the increase in transcript level. Enzyme activity levels for NADH dehydrogenase and cytochrome c oxidase showed a similar trend, albeit of lesser magnitude. These activity levels contrasted with the activity level of an entirely nuclear-encoded mitochondrial enzyme, citrate synthase, which increased not only throughout development but in the older adult tissue. This study indicates that there is a pattern of increasing mitochondrial and nuclear gene expression for OXPHOS enzymes in developing cardiac tissue and decreasing OXPHOS gene expression in the aging heart.
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PMID:Mitochondrial gene expression during bovine cardiac growth and development. 779 43

L-3,4-Dihydroxyphenylalanine (L-dopa) is toxic for human neuroblastoma cells NB69 and its toxicity is related to several mechanisms including quinone formation and enhanced production of free radicals related to the metabolism of dopamine via monoamine oxidase type B. We studied the effect of L-DOPA on activities of enzyme complexes in the electron transport chain (ETC) in homogenate preparations from the human neuroblastoma cell line NB69. As a preliminary step we compared the activity of ETC in cellular homogenates with that of purified mitochondria from NB69 cells and rat brain. Specific activities for complex I, complex II-III, and complex IV in NB69 cells were, respectively, 65, 96, and 32% of those in brain mitochondria. Complex I activity was inhibited in a dose-dependent way by 1-methyl-4-phenylpyridinium ion with an EC50 of approximately 150 microM. Treatment with 0.25 mM L-dopa for 5 days reduces complex IV activity to 74% of control values but does not change either complex I or citrate synthase. Ascorbic acid (1 mM), which protects NB69 cells from L-dopa-induced neurotoxicity, increases complex IV activity to 133% of the control and does not change other ETC complexes. Ascorbic acid also reverses L-dopa-induced reduction of complex IV activity in NB69 cells. This observation might indicate that the protection observed with ascorbic acid is related to complex IV activation. In vitro incubation with L-dopa (0.125-4 mM) for 2 min produced a dose-dependent reduction of complex IV without change in complex I and II-III activities.
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PMID:L-dopa inhibits complex IV of the electron transport chain in catecholamine-rich human neuroblastoma NB69 cells. 783 50

Previous studies have demonstrated impaired complex I activity in platelets from Parkinson's disease (PD) patients who were receiving levodopa and other medications for their disease. Eleven patients with early PD underwent three sequential plateletphereses: while on no medication, after receiving carbidopa/levodopa for 1 month, and after receiving carbidopa/levodopa plus selegiline for 1 additional month. As expected, carbidopa/levodopa and selegiline significantly improved motor function in these patients. Treatment with carbidopa/levodopa alone and carbidopa/levodopa plus selegiline did not affect the activities of complexes I, II/III, and IV and citrate synthetase. These observations support the hypothesis that impaired complex I activity in PD patients is a characteristic of the disease and not due to medications.
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PMID:Carbidopa/levodopa and selegiline do not affect platelet mitochondrial function in early parkinsonism. 785 37

1. Treatment of isolated rat liver mitochondria with methyl methacrylate (MM) produced membrane disruption as evidenced by the release of citrate synthase, and changes in the ultrastructure of mitochondria. 2. At concentration 0.1%, MM uncoupled oxidative phosphorylation as evidenced by stimulation of state 4 respiration supported either by pyruvate plus malate or succinate (+rotenone) and ATP-ase activity in intact mitochondria. 3. At concentration 1% MM stimulated ATP-ase activity in intact mitochondria and succinate (+ rotenone) oxidation at state 4 and was without effect on this substrate oxidation at state 3. 4. MM inhibited pyruvate plus malate oxidation either at state 3 or in the presence of uncoupling agents. 5. MM inhibited the NADH oxidase of electron transport particles at a concentration which failed to inhibit either succinic oxidase or the NADH-ferricyanide reductase activity. 6. The data presented suggest that in the isolated mitochondria MM inhibits NADH oxidation in the vicinity of the rotenone sensitive site of complex I. 7. The general conclusion is that MM may block an electron transport and to uncouple oxidative phosphorylation in rat liver mitochondria. The overall in vitro effect would be to prevent ATP synthesis which could result in cell death under in vivo conditions.
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PMID:Effect of methyl methacrylate on mitochondrial function and structure. 798 36

It has been suggested that myocardial ischemia is associated with a reduction in mitochondrial complex I activity. Respiratory chain enzyme activities were measured in right ventricular biopsies of eight infants with tetralogy of Fallot (TF), left ventricular biopsies of one of the infants with TF, right and left ventricular tissue of seven transplant recipients with atherosclerotic coronary artery disease (CAD), and in right ventricular biopsies of one infant without cardiac pathology (normal control). In right ventricular tissue the specific activity of complexes I+III was significantly lower in TF than in CAD (3.8 +/- 2.7 vs 23 +/- 12 nmol min-1 mg-1 non-collagen protein). In the right ventricular control specimen the activity of complexes I+III was 13.7-fold standard deviation higher than in TF and 1.5-fold higher than in CAD. Left ventricular respiratory chain enzyme activities measured in one patient with TF were lower than those in patients with CAD. Enzyme activities of left ventricular tissue were not significantly different from those of the right ventricle in CAD. The activity of the mitochondrial matrix enzyme citrate synthase did not differ between groups. The data indicate that the prominent reduction of complex I activity found in myocardial ischemia due to CAD is even more pronounced in myocardial hypoxemia due to TF.
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PMID:Mitochondrial respiratory chain enzyme activities in tetralogy of Fallot. 808 70

We isolated and characterized mutants defective in nuo, encoding NADH dehydrogenase I, the multisubunit complex homologous to eucaryotic mitochondrial complex I. By Southern hybridization and/or sequence analysis, we characterized three distinct mutations: a polar insertion designated nuoG::Tn10-1, a nonpolar insertion designated nuoF::Km-1, and a large deletion designated delta(nuoFGHIJKL)-1. Cells carrying any of these three mutations exhibited identical phenotypes. Each mutant exhibited reduced NADH oxidase activity, grew poorly on minimal salts medium containing acetate as the sole carbon source, and failed to produce the inner, L-aspartate chemotactic band on tryptone swarm plates. During exponential growth in tryptone broth, nuo mutants grew as rapidly as wild-type cells and excreted similar amounts of acetate into the medium. As they began the transition to stationary phase, in contrast to wild-type cells, the mutant cells abruptly slowed their growth and continued to excrete acetate. The growth defect was entirely suppressed by L-serine or D-pyruvate, partially suppressed by alpha-ketoglutarate or acetate, and not suppressed by L-aspartate or L-glutamate. We extended these studies, analyzing the sequential consumption of amino acids by both wild-type and nuo mutant cells growing in tryptone broth. During the lag and exponential phases, both wild-type and mutant cells consumed, in order, L-serine and L-aspartate. As they began the transition to stationary phase, both cell types consumed L-tryptophan. Whereas wild-type cells then consumed L-glutamate, glycine, L-threonine, and L-alanine, mutant cells utilized these amino acids poorly. We propose that cells defective for NADH dehydrogenase I exhibit all these phenotypes, because large NADH/NAD+ ratios inhibit certain tricarboxylic acid cycle enzymes, e.g., citrate synthase and malate dehydrogenase.
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PMID:Mutations in NADH:ubiquinone oxidoreductase of Escherichia coli affect growth on mixed amino acids. 815 82

We report the effect of the 11,778 and 3460 base pair mitochondrial DNA mutations, found in Leber's hereditary optic neuropathy (LHON), on platelet mitochondrial respiratory chain enzyme activity. We measured respiratory chain enzyme activities in platelets from 4 patients with the 3460 mutation, 17 patients with the 11,778 mutation and compared them with those of 41 healthy age-matched controls. We observed a 67% (P < 0.001) reduction in the mean NADH CoQ1 reductase (complex I) activity of the 3460 group compared to the control group. It has been shown previously that platelet mitochondrial biochemistry is affected by cigarette smoking. A significant reduction (25%, P < 0.03) in the mean complex I activity of the 11,778 group was only observed when the non-smokers within that group were compared to the non-smoking controls. The effect of smoking observed in this study may explain why previous workers have not observed a decrease in complex I activity associated with the 11,778 mutation. There was no significant change in the activity of complexes II/III or IV with either of these mutations. There was a significant increase (26%, P < 0.008) in citrate synthase (CS) activity with the non-smoking 11,778 group compared to the non-smoking control group, rising to 40% (P < 0.002) in those with this mutation who smoked. This reflects an increase in mitochondrial mass with the 11,778 mutation. This effect was not observed with the 3460 mutation even though the complex deficiency was much more severe.
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PMID:Platelet mitochondrial function in Leber's hereditary optic neuropathy. 819 7

Parkinson's disease (PD) is characterized mainly by a loss of nigrostriatal dopamine neurons. Thus far, the actual physiopathology of PD remains uncertain, although recent studies have found decreased activity of complex I, one of the enzymatic units of the mitochondrial respiratory chain, in various tissues of PD patients. Because most, if not all, of PD patients are treated chronically with levodopa, the precursor of dopamine, and because we have shown previously that catecholamines may alter mitochondrial respiration, we assessed the effects of chronic administration of levodopa on complex I activity in rat brain. We found that chronic administration of levodopa, at a dose used in PD patients, caused a significant reduction in complex I activity while it did not affect the activities of complex II, complex IV, and citrate synthase. Reduction in complex I activity correlated well with catecholamine innervation as the reduction was observed mainly in the striatum and substantia nigra and to a lesser extent in the frontal cortex but not in the cerebellum. Moreover, the levodopa-induced decrease of complex I activity was reversible since activities at 1, 3, and 7 days after the last injection showed a progressive return to control values. Incubation of whole brain mitochondria in vitro showed that both levodopa and dopamine inhibit complex I activity in a dose- and time-dependent manner. In contrast, other compounds such as homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 3-O-methyl-dopa were minimally effective. Reduced glutathione, ascorbate, superoxide dismutase, and catalase prevented the effect of levodopa and dopamine on complex I. Various inhibitors of monoamine oxidase also prevented the effect of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Chronic levodopa administration alters cerebral mitochondrial respiratory chain activity. 823 66

It has been hypothesized that some of the functional impairments associated with aging are the result of increasing oxidative damage to mitochondrial DNA that produces defects in oxidative phosphorylation. To test this hypothesis, we examined the enzymes that catalyze oxidative phosphorylation in crude mitochondrial preparations from frontoparietal cortex of 20 rhesus monkeys (5-34 years old). Samples were assayed for complex I, complex II-III, complex IV, complex V, and citrate synthase activities. When enzyme activities were corrected for citrate synthase activities (to account for variable degrees of mitochondrial enrichment), linear regression analysis demonstrated a significant negative correlation of the activities of complex I (p < 0.002) and complex IV (p < 0.03) with age but no significant change in complex II-III or complex V activities. Relative to animals 6.9 +/- 0.9 years old (n = 7), the citrate synthase-corrected activity of complex I was reduced by 17% in animals 22.5 +/- 0.9 years old (n = 6) (p < 0.05) and by 22% in animals 30.7 +/- 0.9 years old (n = 7) (p < 0.01). Similar age-related reductions in the activities of complexes I and IV were obtained when enzyme activities were corrected for complex II-III activity. These findings show an age-associated progressive impairment of mitochondrial complex I and complex IV activities in cerebral cortices of primates.
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PMID:Age-dependent impairment of mitochondrial function in primate brain. 847 11


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