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:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an analysis of nitric oxide (.NO) production and toxicity, chicken macrophage-generated .NO inhibited mitochondrial activity in both .NO-producing macrophages themselves and lymphoid tumor targets. However, differences in targeting of mitochondrial toxicity were observed among these cells. Two chicken macrophage cell lines, HD11 and MQ-NCSU, produced .NO (measured as nitrite) dependent upon concentrations of L-arginine and bacterial endotoxin (lipopolysaccharide). Mitochondrial activity was negatively correlated with the amount of .NO produced. Using a modified MTT assay, .NO induced suppression in two mitochondrial complexes. Mitochondrial activity was significantly suppressed among HD11 cells receiving LPS alone (complex I, 63.0 +/- 5.5% suppression; complex II, 27.9 +/- 5.2%). In contrast, mitochondrial activities in samples receiving LPS plus inhibitor, NG-nitro-L-arginine methyl ester (NAME; 5 mM) or 2,4-diamino-6-hydroxypyrimidine (DAHP; 5 mM), were not significantly different from control values. When HD11 macrophages were cocultured with lymphoblastoid tumor targets, RECC-CU60 (T cell) or LSCC-RP9 (B cell), adding LPS (1 microgram/ml), tumor cell mitochondrial activity was significantly suppressed. In the generator macrophages, complex I was more suppressed than complex II, whereas in lymphoid targets no such difference was observed. These results indicate that .NO inhibits complex I and II mitochondrial activity but that differential targeting can occur among chicken leukocyte populations.
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PMID:Nitric oxide (.NO)-induced mitochondrial injury among chicken .NO-generating and target leukocytes. 802 70

The activities of selected enzymes of the respiratory chain system in Onchocerca fasciata (Filarioidea: Onchocercidae) have been investigated histochemically. Thus, the localization and distributions of NADH dehydrogenase (EC 1.6.99.3), succinate dehydrogenase (SDH) (EC 1.3.99.1) and cytochrome oxidase (EC 1.9.3.1) were investigated in various tissues of the adult female worm by employing MTT, Nitro BT (dehydrogenases) and DAB (cytochrome oxidase). Different tissues varied considerably in their enzymatic activities. The hypodermis and reproductive tissues showed strong and identical localization of NADH and SDH dehydrogenase activities reflecting high metabolic rates. Little or no dehydrogenase activities were observed in the intestine and cuticle. In contrast to the two dehyrogenases, no activity was observed for cytochrome oxidase in any of the tissues in adult or embryonic stages of the worm. The significance of these results with respect to the energy metabolism of the worm is discussed. It is suggested that O. fasciata lacks a classical, mammalian-type respiratory pathway and that oxidative phosphorylation is of no importance as an energy generating pathway in this essentially anaerobic parasite.
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PMID:Onchocerca fasciata: histochemical demonstration of succinate and NADH dehydrogenase. 896 Jan 99

In vivo administration of either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (MA) produces damage to the dopaminergic nervous system which may be due in part to the generation of reactive oxygen species (ROS). The resistance of superoxide dismutase (SOD) over-expressing transgenic mice to the effects of both MPTP and MA suggests the involvement of superoxide in the resulting neurotoxicity of both compounds. Superoxide can be converted by SOD to hydrogen peroxide, which itself can cause cellular degeneration by reacting with free iron to produce highly reactive hydroxyl radicals resulting in damage to proteins, nucleic acids and membrane phospholipids. Hydrogen peroxide has also been reported to be produced via inhibition of NADH dehydrogenase by MPP + formed during oxidation of MPTP by MAO-B and by dopamine auto-oxidation following MA-induced dopamine release from synaptic vesicles within nerve terminals. To test whether hydrogen peroxide is an important factor in the toxicity of either of these two neurotoxins, we created clonal PC12 lines expressing elevated levels of the hydrogen peroxide-reducing enzyme glutathione peroxidase (GSHPx). Elevation of GSHPx levels in PC12 was found to diminish the rise in ROS levels and lipid peroxidation resulting from MA but not MPTP treatment. Elevated levels of GSHPx also appeared to prevent decreases in transport-mediated dopamine uptake produced via MA administration as well as to attenuate toxin-induced cell loss as measured by either MTT reduction or LDH release. Our data, therefore, suggest that hydrogen peroxide production likely contributes to MA toxicity in dopaminergic neurons.
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PMID:Elevated expression of glutathione peroxidase in PC12 cells results in protection against methamphetamine but not MPTP toxicity. 919 Oct 89

Indicators of mitochondrial function were studied in two different cell culture models of cis-diamminedichloroplatinum-II (CDDP) resistance: the intrinsically resistant human ovarian cancer cell line CI-80-13S, and resistant clones (HeLa-S1a and HeLa-S1b) generated by stable expression of the serine protease inhibitor-plasminogen activator inhibitor type-2 (PAI-2), in the human cervical cancer cell line HeLa. In both models, CDDP resistance was associated with sensitivity to killing by adriamycin, etoposide, auranofin, bis[1,2-bis(diphenylphosphino)ethane]gold(I) chloride ([Au(DPPE)2]Cl), CdCl2 and the mitochondrial inhibitors rhodamine-123 (Rh123), dequalinium chloride (DeCH), tetraphenylphosphonium (TPP), and ethidium bromide (EtBr) and with lower constitutive levels of ATP. Unlike the HeLa clones, CI-80-13S cells were additionally sensitive to chloramphenicol, 1-methyl-4-phenylpyridinium ion (MPP+), rotenone, thenoyltrifluoroacetone (TTFA), and antimycin A, and showed poor reduction of 1-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), suggesting a deficiency in NADH dehydrogenase and/or succinate dehydrogenase activities. Total platinum uptake and DNA-bound platinum were slightly lower in CI-80-13S than in sensitive cells. The HeLa-S1a and HeLa-S1b clones, on the other hand, showed poor reduction of triphenyltetrazolium chloride (TTC), indicative of low cytochrome c oxidase activity. Total platinum uptake by HeLa-Sla was similar to HeLa, but DNA-bound platinum was much lower than for the parent cell line. The mitochondria of CI-80-13S and HeLa-S1a showed altered morphology and were fewer in number than those of JAM and HeLa. In both models, CDDP resistance was associated with less platinum accumulation and with mitochondrial and membrane defects, brought about one case with expression of a protease inhibitor which is implicated in tumor progression. Such markers may identify tumors suitable for treatment with gold phosphine complexes or other mitochondrial inhibitors.
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PMID:Serine protease inhibition and mitochondrial dysfunction associated with cisplatin resistance in human tumor cell lines: targets for therapy. 926 20

The damage to the central nervous system that is observed after administration of either methamphetamine (METH) or 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is known to be linked to dopamine (DA). The underlying neurotoxicity mechanism for both METH and MPP+ seem to involve free radical formation and impaired mitochondrial function. The MPP+ is thought to selectively kill nigrostriatal dopaminergic neurons by inhibiting mitochondrial complex I, with cell death being attributed to oxidative stress damage to these vulnerable DA neurons. In the present study, MPP+ was shown to significantly inhibit the response to MTT by cultured PC12 cells. This inhibitory action of MPP+ could be partially reversed by the co-incubation of the cells with the acetylated form of carnitine, acetyl-L-carnitine (ALC). Since at least part of the toxic action of MPP+ is related to mitochondrial inhibition, the partial reversal of the inhibition of MTT response by ALC could involve a partial restoration of mitochondrial function. The role carnitine derivatives, such as ALC, play in attenuating MPP+ and METH-evoked toxicity is still under investigation to elucidate the contribution of mitochondrial dysfunction in mechanisms of neurotoxicity.
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PMID:Role of mitochondrial dysfunction in neurotoxicity of MPP+: partial protection of PC12 cells by acetyl-L-carnitine. 1554 26

Mutations of Cu/Zn superoxide dismutase (SOD1) are found in patients with familial amyotrophic lateral sclerosis (FALS). A cellular model of FALS was developed by stably transfecting the motor neuron-like cell line NSC-34 with human wild type (wt) or mutant (G93A) SOD1. Expression levels of G93ASOD1 were close to those seen in the human disease. The presence of G93ASOD1 did not alter cell proliferation but toxicity was evident when the cells were in the growth plateau phase. Flow cytometry analysis indicated that, in this phase, G93ASOD1 significantly lowered viability and that the level of reactive oxygen species was significantly higher in living G93ASOD1 cells compared to wt SOD1 cells. Biparametric analysis of mitochondrial membrane potential and viability of transfected cells highlighted a peculiar population of damaged cells with strong mitochondrial depolarization in the G93ASOD1 cells. Mitochondrial function seemed related to the level of the mutant protein since MTT conversion decreased when expression of G93ASOD1 doubled after treating cells with sodium butyrate. The mutant protein rendered G93ASOD1 cells more sensitive to mitochondrial dysfunction induced by stimuli that alter cellular free radical homeostasis, like serum withdrawal, depletion of glutathione by ethacrynic acid or rotenone-mediated inhibition of complex I of the mitochondrial electron transport chain. In conclusion, even a small amount of mutant SOD1 put motor neurons in a condition of oxidative stress and mitochondrial damage that causes cell vulnerability and death.
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PMID:Low levels of ALS-linked Cu/Zn superoxide dismutase increase the production of reactive oxygen species and cause mitochondrial damage and death in motor neuron-like cells. 1585 May 89

Several studies on mitochondrial functions following brief exposure (5-15 min) to dopamine (DA) in vitro have produced extremely variable results. In contrast, this study demonstrates that a prolonged exposure (up to 2 h) of disrupted or lysed mitochondria to DA (0.1-0.4 mM) causes a remarkable and dose-dependent inhibition of complex I and complex IV activities. The inhibition of complex I and complex IV activities is not prevented by the antioxidant enzyme catalase (0.05 mg/ml) or the metal-chelator diethylenetriaminepentaacetic acid (0.1 mM) or the hydroxyl radical scavengers like mannitol (20 mM) and dimethyl sulphoxide (20 mM) indicating the non-involvement of *OH radicals and Fenton's chemistry in this process. However, reduced glutathione (5 mM), a quinone scavenger, almost completely abolishes the DA effect on mitochondrial complex I and complex IV activities, while tyrosinase (250 units/ml) which catalyses the conversion of DA to quinone products dramatically enhances the former effect. The results suggest the predominant involvement of quinone products instead of reactive oxygen radicals in long-term DA-mediated inactivation of complex I and complex IV. This is further indicated from the fact that significant amount of quinones and quinoprotein adducts (covalent adducts of reactive quinones with protein thiols) are formed during incubation of mitochondria with DA. Monoamine oxidase A (MAO-A) inhibitor clorgyline also provides variable but significant protection against DA induced inactivation of complex I and complex IV activities, presumably again through inhibition of quinoprotein formation. Mitochondrial ability to reduce tetrazolium dye 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) in presence of a respiratory substrate like succinate (10 mM) is also reduced by nearly 85% following 2 h incubation with 0.4 mM DA. This effect of DA on mitochondrial function is also dose-dependent and presumably mediated by quinone products of DA oxidation. The mitochondrial dysfunction induced by dopamine during extended periods of incubation as reported here have important implications in the context of dopaminergic neuronal death in Parkinson's disease (PD).
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PMID:Inhibition of rat brain mitochondrial electron transport chain activity by dopamine oxidation products during extended in vitro incubation: implications for Parkinson's disease. 1592 94

Both genetic and environmental factors are involved in the pathogenesis of Parkinsonos disease (PD). Epidemiological studies showed that environmental factors shared with the common mechanisms of resulting in alpha-synuclein aggregation by inhibiting complex I of mitochondria and leading to oxidative stress. To investigate the relationship between alpha-synuclein and oxidative stress, we used human dopaminergic SH-SY5Y cells transfected with alpha-synuclein-enhanced green fluorescent protein (EGFP). alpha-synuclein gene expression was determined by immunocytochemistry and real-time quantitative PCR. Both SH-SY5Y and alpha-synuclein overexpressed SH-SY5Y (SH-SY5Y/Syn) cells were treated with various concentrations of rotenone for different time. Cell viability and oxidative stress were detected by MTT assay and DCF assay. Superoxide dismutase (SOD) activity was assessed with xanthine peroxidase method. Cell apoptosis was detected with flow cytometry. Results showed that alpha-synuclein gene was constantly overexpressed in SH-SY5Y/Syn cells. After treatment with rotenone, both cell viability and complex I activity in these cells were reduced in a concentration-dependent manner. Oxidative stress was also found in these cells. Compared with SH-SY5Y cells, SOD activity in SH-SY5Y/Syn cells was increased distinctly (P<0.05) and alpha-synuclein significantly attenuated rotenone-induced cell apoptosis. These results suggest that the alpha-synuclein overexpression in SH-SY5Y cells has a tendency to partially resist oxidative stress induced by rotenone and this response may assist cell survival.
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PMID:[Overexpression of alpha-synuclein in SH-SY5Y cells partially protected against oxidative stress induced by rotenone]. 1704 25

1-Methyl-4-phenylpyridinium ion (MPP+), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with an elevation of intracellular reactive oxygen species (ROS) and apoptosis. L-carnitine plays an integral role in attenuating the brain injury associated with mitochondrial neurodegenerative disorders. The present study investigates the effects of L-carnitine against the toxicity of MPP+ in rat forebrain primary cultures. Cells in culture were treated for 24 h with 100, 250, 500 and 1000 microM MPP+ alone or co-incubated with L-carnitine. MPP+ produced a dose-related increase in DNA fragmentation as measured by cell death ELISA (enzyme-linked immunosorbent assay), an increase in the number of TUNEL (terminal dUTP nick-end labeling)-positive cells and a reduction in the mitochondrial metabolism of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). No significant effect was observed with the release of lactate dehydrogenase (LDH), indicating that cell death presumably occurred via apoptotic mechanisms. Co-incubation of MPP+ with L-carnitine significantly reduced MPP+-induced apoptosis. Western blot analyses showed that neurotoxic concentrations of MPP+ decreased the ratio of BCL-X(L) to Bax and decreased the protein levels of polysialic acid neural cell adhesion molecules (PSA-NCAM), a neuron specific marker. L-carnitine blocked these effects of MPP+ suggesting its potential therapeutic utility in degenerative disorders such as Parkinson's disease, Alzheimer's disease, ornithine transcarbamylase deficiency and other mitochondrial diseases.
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PMID:L-carnitine protects neurons from 1-methyl-4-phenylpyridinium-induced neuronal apoptosis in rat forebrain culture. 1708 38

The neuroprotective effects of catalpol, an iridoid glycoside present in the roots of Rehmannia glutinosa, on 1-methyl-4-phenylpyridinium (MPP(+))-induced oxidative stress in cultured mesencephalic neurons, especially dopaminergic neurons, were investigated. Exposure of mesencephalic neurons to 10microM MPP(+) induced a leakage of lactate dehydrogenase (LDH) and decreased cell viability, measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Catalpol increased neuron viability and markedly attenuated MPP(+)-induced dopaminergic neuron death in a dose-dependent manner. In order to clarify the neuroprotective mechanism of catalpol, mitochondrial function, the activities of endogenous antioxidants and the lipid peroxide content were measured. The results indicated that catalpol prevented the MPP(+)-induced inhibition of complex I activity and the loss of mitochondrial membrane potential. In addition, catalpol reduced the content of lipid peroxide and increased the activity of glutathione peroxidase and superoxide dismutase. Taken together, the above results suggest that catalpol may be a candidate drug for the treatment of oxidative stress-induced neurodegenerative disease.
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PMID:Neuroprotective effect of catalpol against MPP(+)-induced oxidative stress in mesencephalic neurons. 1751 20


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