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)

Drosophila melanogaster displays an age-associated increase in oxidative damage and a decrease in mitochondrial transcripts. To determine if these changes result in energy production deficiencies, we measured the electron transport system (ETS) enzyme activity, and ATP levels with age. No statistically significant influences of age on activities of complexes I and II or citrate synthase were observed. In contrast, from 2 to 45 days post-eclosion, declines were found in complex IV cytochrome c oxidase activity (COX, 40% decline) and ATP abundance (15%), while lipid peroxidation increased 71%. We next examined flies that were either genetically or chemically oxidatively stressed to determine the effect on levels of mitochondrial-encoded cytochrome oxidase I RNA (coxI) and COX activity. A catalase null mutant line had 48% of coxI RNA compared to the wild type. In Cu/Zn superoxide dismutase (cSOD) null flies, the rate of coxI RNA decline was greater than in controls. CoxI RNA also declined with increasing hydrogen peroxide (H2O2) treatment, which was reflected in reduced cytochrome c oxidase (COX) activity. These results show that oxidative stress is closely associated with reductions in mitochondrial transcript levels and support the hypothesis that oxidative stress may contribute to mitochondrial dysfunction and aging in D. melanogaster.
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PMID:Oxidative stress and aging reduce COX I RNA and cytochrome oxidase activity in Drosophila. 980 Oct 75

We analyzed mitochondrial DNA (mtDNA) from 7 patients in four families with adult onset limb-girdle type mitochondrial myopathy to clarify their genetic background. The patients, 2 men and 5 women, showed common clinical features, characterized by isolated skeletal myopathy, high serum creatine kinase level, ragged-red fibers and cytochrome c oxidase-defective fibers. Analysis of muscle biopsy specimens indicated that cytochrome c oxidase activity was decreased relative to that of citrate synthase in 5 of the 7 patients. Southern blotting and direct sequence analyses showed an A-to-G homoplasmic transition at np8291 and intergenic COII/tRNA (Lys) 9bp deletion in all patients. This substitution was detected in only 2 of 600 control individuals including healthy subjects and patients with other neuromuscular disorders; these 2 individuals had diabetes mellitus and myotonic dystrophy, respectively. Consequently, the mtDNA transition at np8291 was a rare polymorphism. However, the 7 patients we studied had identical clinical, pathological, biochemical, and genetic features. Therefore, limb-girdle type mitochondrial myopathy with this rare polymorphism may form a subgroup of adult onset mitochondrial myopathy.
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PMID:Adult onset limb-girdle type mitochondrial myopathy with a mitochondrial DNA np8291 A-to-G substitution. 1031 90

Malignant mesothelioma cells contain elevated levels of manganese superoxide dismutase (MnSOD) and are highly resistant to oxidants compared to non-malignant mesothelial cells. Since the level of cellular free radicals may be important for cell survival, we hypothesized that the increase of MnSOD in the mitochondria of mesothelioma cells may alter the free radical levels of these organelles. First, MnSOD activity was compared to the activities of two constitutive mitochondrial enzymes; MnSOD activity was 20 times higher in the mesothelioma cells than in the mesothelial cells, whereas the activities of citrate synthase and cytochrome c oxidase did not differ significantly in the two cell lines. This indicates that the activity of MnSOD per mitochondrion was increased in the mesothelioma cells. Superoxide production was assayed in the isolated mitochondria of these cells using lucigenin chemiluminescence. Mitochondrial superoxide levels were significantly lower (72%) in the mesothelioma cells compared to the mesothelial cells. Oxidant production in intact cells, assayed by fluorimetry using 2',7'-dichlorodihydrofluorescein as a fluorescent probe, did not differ significantly between these cells. We conclude that mitochondrial superoxide levels are lower in mesothelioma cells compared to nonmalignant mesothelial cells, and that this difference may be explained by higher MnSOD activity in the mitochondria of these cells. Oxidant production was not different in these cells, which may be due to the previously observed increase in H2O2-scavenging mechanisms of mesothelioma cells.
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PMID:Generation of reactive oxygen species by human mesothelioma cells. 1038 73

Different severe disorders of cytochrome c oxidase (COX) have been described in children, but only the defects with autosomal inheritance are suitable for prenatal diagnosis. To perform prenatal diagnosis of fatal infantile COX deficiency a complex approach has been used which combined determination of the genetic origin of the defect, and detailed analysis of the function, content and subunit composition of the enzyme in cultured fetal cells. The tissues and cultured fibroblasts of the patient with Leigh's syndrome showed a COX deficiency of systemic character. The decrease of COX activity to 5-11 per cent was accompanied by proportionally decreased content of the assembled COX enzyme. With the help of transmitochondrial cybrids derived from patient fibroblasts it was proven that the COX defect was of nuclear origin. In a successive pregnancy, the function of oxidative phosphorylation (OXPHOS) was analysed in cultured amniocytes by substrate-stimulated ATP production and COX activity was compared with the activity of citrate synthase. The amount and composition of OXPHOS complexes was estimated by two-dimensional (Blue Native/SDS) polyacrylamide gel electrophoresis and was verified immunochemically with specific antibodies. Three independent lines of evidence provided us with reliable data on the function of COX and OXPHOS in fetal cells which were sufficient to rule out the expected enzymatic defect within three weeks after amniocentesis.
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PMID:Complex approach to prenatal diagnosis of cytochrome c oxidase deficiencies. 1041 72

We report a new type of fatal mitochondrial disorder caused by selective deficiency of mitochondrial ATP synthase (ATPase). A hypotrophic newborn from a consanguineous marriage presented severe lactic acidosis, cardiomegaly and hepatomegaly and died from heart failure after 2 days. The activity of oligomycin-sensitive ATPase was only 31-34% of the control, both in muscle and heart, but the activities of cytochrome c oxidase, citrate synthase and pyruvate dehydrogenase were normal. Electrophoretic and western blot analysis revealed selective reduction of ATPase complex but normal levels of the respiratory chain complexes I, III and IV. The same selective deficiency of ATPase was found in cultured skin fibroblasts which showed similar decreases in ATPase content, ATPase hydrolytic activity and level of substrate-dependent ATP synthesis (20-25, 18 and 29-33% of the control, respectively). Pulse-chase labelling of patient fibroblasts revealed low incorporation of [(35)S]methionine into assembled ATPase complexes, but increased incorporation into immunoprecipitated ATPase subunit beta, which had a very short half-life. In contrast, no difference was found in the size and subunit composition of the assembled and newly produced ATPase complex. Transmitochondrial cybrids prepared from enucleated fibroblasts of the patient and rho degrees cells derived from 143B. TK(-)human osteosarcoma cells fully restored the ATPase activity, ATP synthesis and ATPase content, when compared with control cybrids. Likewise, the pattern of [(35)S]methionine labelling of ATPase was found to be normal in patient cybrids. We conclude that the generalized deficiency of mitochondrial ATPase described is of nuclear origin and is caused by altered biosynthesis of the enzyme.
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PMID:A novel deficiency of mitochondrial ATPase of nuclear origin. 1048 64

Defects in mitochondrial oxidative metabolism, in particular decreased activity of cytochrome c oxidase, have been demonstrated in Alzheimer's disease, and after the expression of the amyloid precursor protein (APP) in cultured cells, suggesting that mitochondria might be involved in beta-amyloid toxicity. Recent evidence suggests that the proteolysis of APP to generate beta-amyloid is at least in part intracellular, preceding the deposition of extracellular fibrils. We have therefore investigated the effect of incubation of isolated rat brain mitochondria with the beta-amyloid fragment 25-35 (100 microM) on the activities of the mitochondrial respiratory chain complexes I, II-III, IV (cytochrome c oxidase) and citrate synthase. The peptide caused a rapid, dose-dependent decrease in the activity of complex IV, white it had no effect on the activities on any of the other enzymes tested. The reverse sequence peptide (35-25) had no effect on any of the activities measured. We conclude that inhibition of mitochondrial complex IV might be a contributing factor to the pathogenesis of Alzheimer's disease.
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PMID:beta-Amyloid fragment 25-35 selectively decreases complex IV activity in isolated mitochondria. 1048 79

The oxidative capacity of the liver, the heart and skeletal muscles for fatty acids were investigated in preruminant calves fed for 19 d on a milk-replacer containing either coconut oil (CO, rich in 12:0) or tallow (rich in 16:0 and 18:1). Weights of the total body and tissues did not differ significantly between the two groups of animals but plasma glucose and insulin concentrations were lower in the CO group. Feeding on the CO diet induced an 18-fold increase in the hepatic concentration of triacylglycerols. Rates of total and peroxisomal oxidation of [1-14C]laurate, [1-14C]palmitate and [1-14C]oleate were measured in fresh tissue homogenates. Higher rates of total oxidation in liver homogenate and of peroxisomal oxidation in liver, heart and rectus abdominis muscle homogenates were observed with laurate used as substrate. Furthermore, the relative contribution of peroxisomes to total oxidation was 1.9-fold higher in the liver and in the heart with laurate than with oleate or palmitate. Finally, the peroxisomal oxidation rate of oleate was 1.5-fold higher in the hearts of calves fed on the CO diet. Whatever the tissue, citrate synthase (CS, EC 4.1.3.7) and cytochrome c oxidase (COX, EC 1.9.3.1) activities were similar between the two groups of calves but the COX: CS activity ratio was lower in the liver of the CO group. In conclusion, laurate is better catabolized by peroxisomes than long-chain fatty acids, especially in the liver. Elongation of lauric acid after partial oxidation might explain the hepatic triacylglycerol accumulation in calves fed on the CO diet.
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PMID:Effects of dietary coconut oil on fatty acid oxidation capacity of the liver, the heart and skeletal muscles in the preruminant calf. 1065 79

Heat shock proteins (HSPs) are expressed when cells are exposed to various types of stress and they may provide protection against cellular insult. Previous data have shown increases in HSP expression following acute exhaustive exercise in rats (Locke et al. 1990, 1995; Salo et al. 1991) and humans (Liu et al. 1999); however, it is not known if chronic exercise will increase resting levels of HSPs. The purpose of this study was to determine if basal protein levels of HSP 72/73 and HSP 60 are increased in cardiac and skeletal muscle of endurance trained Fischer 344 rats. Heart, soleus (SOL) and lateral gastrocnemius (LG) muscles were removed and hearts were sectioned into left ventricle (LV), right ventricle (RV) and atria (AT). Endurance training improved myocardial citrate synthase activity by 88, 90 and 77% and cytochrome c oxidase activity by 58, 51 and 89% in LV, RV and AT, respectively. LV and RV oxidative enzyme activities were greater when compared to AT for both trained and untrained rats (P < 0.05). HSP 72/73 expression was significantly greater (P < 0.05) in LV, RV and SOL from endurance trained versus from control rats (26, 45 and 67%, respectively). HSP 60 was also increased (P < 0.05) in LV, RV and SOL in trained relative to untrained rats. HSP 72/73 and HSP 60 were unchanged in AT and LG after training. These results indicate that endurance training increases the basal expression of stress proteins and this observation is consistent with the hypothesis that endurance training may activate a protective mechanism to stress.
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PMID:Heat shock protein expression is increased in cardiac and skeletal muscles of Fischer 344 rats after endurance training. 1066 98

Numerous studies have reported effects of antiviral nucleoside analogs on mitochondrial function, but they have not correlated well with the observed toxic side effects. By comparing the effects of the five Food and Drug Administration-approved anti-human immunodeficiency virus nucleoside analogs, zidovudine (3'-azido-3'-deoxythymidine) (AZT), 2',3'-dideoxycytidine (ddC), 2', 3'-dideoxyinosine (ddI), 2',3'-didehydro-2',3'-deoxythymidine (d4T), and beta-L-2',3'-dideoxy-3'-thiacytidine (3TC), as well as the metabolite of AZT, 3'-amino-3'-deoxythymidine (AMT), on mitochondrial function in a human hepatoma cell line, this issue has been reexamined. Evidence for a number of mitochondrial defects with AZT, ddC, and ddI was found, but only AZT induced a marked rise in lactic acid levels. Only in mitochondria isolated from AZT (50 microM)-treated cells was significant inhibition of cytochrome c oxidase and citrate synthase found. Our investigations also demonstrated that AZT, d4T, and 3TC did not affect the synthesis of the 11 polypeptides encoded by mitochondrial DNA, while ddC caused 70% reduction of total polypeptide content and ddI reduced by 43% the total content of 8 polypeptides (including NADH dehydrogenase subunits 1, 2, 4, and 5, cytochrome c oxidase subunits I to III, and cytochrome b). We hypothesize that in hepatocytes the reserve capacity for mitochondrial respiration is such that inhibition of respiratory enzymes is unlikely to become critical. In contrast, the combined inhibition of the citric acid cycle and electron transport greatly enhances the dependence of the cell on glycolysis and may explain why apparent mitochondrial dysfunction is more prevalent with AZT treatment.
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PMID:Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells. 1068 9

The quantification of mitochondrial enzyme activities in skeletal muscle samples of patients suspected of having mitochondrial myopathies is problematic. Therefore, we have evaluated different methods for the determination of activities cytochrome c oxidase and NADH:CoQ oxidoreductase in human skeletal muscle samples. The measurement of cytochrome c oxidase activity in the presence of 200 microM ferrocytochrome c and the detection of NADH:CoQ oxidoreductase as rotenone-sensitive NADH:CoQ(1) reductase resulted in comparable citrate synthase-normalized respiratory chain enzyme activities of both isolated mitochondria and homogenates from control human skeletal muscle samples. These methods allowed the precise detection of deficiencies of respiratory chain enzymes in skeletal muscle of two patients harboring only 20 and 27% of deleted mitochondrial DNA, respectively. Therefore, citrate synthase-normalized respiratory chain activities can serve as stable reference values for the determination of a putative mitochondrial defect in human skeletal muscle.
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PMID:Evaluation of methods for the determination of mitochondrial respiratory chain enzyme activities in human skeletal muscle samples. 1068 30


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