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)

We describe the effects of the neurotoxin 3-nitropropionic acid (3-NPA) on fatty acid oxidation in neonatal rat brain astrocytes in primary culture, using a sensitive assay for beta-oxidation which depends on the release of 3H2O from [9,10(n)-3H]palmitic acid. 3-NPA is a suicide inhibitor of succinate dehydrogenase, a constituent of both Krebs cycle and complex II of the mitochondrial respiratory chain. It is widely distributed in plants and fungi. Neurotoxicity of 3-NPA to humans and animals, leading to selective neuronal cell death, appears mediated by the reduced level of ATP induced by the toxin. We demonstrated that 3-NPA can also impair energy metabolism in astrocytes. Exposure of astroglial cells in culture to 3-NPA leads to inhibition of the release of 3H2O from [9,10(n)-3H]palmitic acid. Addition of 2 mM 3-NPA to the culture medium caused a rapid decrease in beta-oxidation activity, which reached a plateau after 90 min. This inhibition was concentration-dependent. Concentration as low as 0.05 mM for 5 h significantly decreased beta-oxidation activity (25% inhibition). Half-maximal inhibition was obtained after treatment with 0.5 mM 3-NPA, and 3 mM induced a maximal response (63% inhibition) 3-NPA is clearly a potent inhibitor of beta-oxidation activity. We also show that 3-NPA 3 mM inhibits partially complex II (succinate ubiquinone reductase) and aspartate aminotransferase by 60 and 49% after 4 h treatment respectively. It has been shown that fatty acid is the preferred substrate for energy production in cultured astrocytes from developing brain. As astrocytes may also provide substrates alternative for energy metabolism in neurons and oligodendrocytes, it is likely that the inhibition of beta-oxidation by 3-NPA may contribute significantly to the damage induced by this toxin in the central nervous system.
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PMID:Inhibition of fatty acid beta-oxidation in rat brain cultured astrocytes exposed to the neurotoxin 3-nitropropionic acid. 921 76

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a dopaminergic neurotoxin which inhibits mitochondrial complex I. 3-Nitropropionic acid (3-NPA) inhibits mitochondrial complex II and produces specific striatal lesions. In order to produce a combined striatal neuronal and dopaminergic afferent lesion, we administered both toxins simultaneously to the mouse. The combination brought about a lesion in the striatum that was not simply additive of the two combined toxins. Intriguingly, a group of striatal neurons became immunoreactive to tyrosine hydroxylase after day 1. Some of them were clearly visible up to the dendritic details. Immuno-electron microscopy indicated that the tyrosine hydroxylase-positive striatal neurons contained densely immunoreactive polyribosomes. Reverse transcriptase-polymerase chain reaction analysis indicated the up-regulation of tyrosine hydroxylase mRNA in the treated striatum. These neurons were also immunoreactive to aromatic L-amino acid decarboxylase.We conclude that the combined administration of MPTP and 3-NPA caused a more profound damage to the nigro-striatal dopaminergic system, and thus some striatal neurons capable of up-regulating tyrosine hydroxylase were induced to produce dopamine, probably to compensate for the dopamine depletion.
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PMID:Neuronal ectopic expression of tyrosine hydroxylase in the mouse striatum by combined administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 3-nitropropionic acid. 1173 97

3-Nitropropionic acid (3-NPA), an inhibitor of succinate dehydrogenase (SDH) at complex II of the mitochondrial electron transport chain induces cellular energy deficit and oxidative stress-related neurotoxicity. In the present study, we identified the site of reactive oxygen species production in mitochondria. 3-NPA increased O2- generation in mitochondria respiring on the complex I substrates pyruvate+malate, an effect fully inhibited by rotenone. Antimycin A increased O2- production in the presence of complex I and/or II substrates. Addition of 3-NPA markedly increased antimycin A-induced O2- production by mitochondria incubated with complex I substrates, but 3-NPA inhibited O2- formation driven with the complex II substrate succinate. At 0.6 microM, myxothiazol inhibits complex III, but only partially decreases complex I activity, and allowed 3-NPA-induced O2- formation; however, at 40 microM myxothiazol (which completely inhibits both complexes I and III) eliminated O2- production from mitochondria respiring via complex I substrates. These results indicate that in the presence of 3-NPA, mitochondria generate O2- from a site between the ubiquinol pool and the 3-NPA block in the respiratory complex II.
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PMID:Localization of superoxide anion production to mitochondrial electron transport chain in 3-NPA-treated cells. 1701 37

The present investigation was designed to determine the efficacy of Bacopa monnieri (Brahmi; BM) to offset 3-nitropropionic acid (3-NPA) induced oxidative stress and mitochondrial dysfunction in dopaminergic (N27) cells and prepubertal mouse brain. Pretreatment of N27 cells with BM ethanolic extract (BME) significantly attenuated 3-NPA-induced cytotoxicity. Further, we determined the degree of oxidative stress induction, redox status, enzymic antioxidants, and protein oxidation in the striatal mitochondria of mice given BME prophylaxis followed by 3-NPA challenge. While 3-NPA-induced marked oxidative stress in the mitochondria of the striatum, BME prophylaxis markedly prevented 3-NPA-induced oxidative dysfunctions and depletion of reduced glutathione and thiol levels. The activities of antioxidant enzymes (superoxide dismutase, glutathione peroxidase, glutathione reductase, thioredoxin reductase), Na(+),K(+)-ATPase, and citric acid cycle enzymes in the striatum discernible among 3-NPA mice were significantly restored with BME prophylaxis. Interestingly, BME offered protection against 3-NPA-induced mitochondrial dysfunctions as evidenced by the restoration of the activities of ETC enzymes (NADH:ubiquinone oxidoreductase, NADH:cytochrome c reductase, succinate-ubiquinone oxidoreductase, and cytochrome c oxidase) and mitochondrial viability. We hypothesize that the neuroprotective effects of BME may be wholly or in part related to its propensity to scavenge free radicals, maintain redox status, and upregulate antioxidant machinery in striatal mitochondria.
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PMID:Pretreatment with Bacopa monnieri extract offsets 3-nitropropionic acid induced mitochondrial oxidative stress and dysfunctions in the striatum of prepubertal mouse brain. 2247 17

Mitochondrial dysfunction is critical for neurodegeneration in movement disorders. Neurotoxicological models recapitulating movement disorder involve mitochondrial damage including inhibition of mitochondrial complexes. Previously, we demonstrated that neurotoxic models of Parkinson's disease and Manganism showed distinct morphological, electrophysiological and molecular profile indicating disease-specific characteristics. In a recent study, we demonstrated that the transcriptomic changes triggered by the neurotoxic mitochondrial complex II inhibitor 3-nitropropionic acid (3-NPA), was significantly different from the profile induced by the neurotoxic mitochondrial complex I inhibitor 1-methyl-4- phenylpyridinium (MPP+) and mitochondrial toxin Manganese (Mn). Among the plausible pathways, we surmised that epigenetic mechanisms could contribute to 3-NPA specific transcriptomic profile. To address this, we assessed global and individual lys-specific acetylation profile of Histone H3 and H4 in the 3-NPA neuronal cell model. Our data revealed histone acetylation profile unique to the 3-NPA model that was not noted in the MPP+ and Mn models. Among the individual lys, Histone H3K56 showed robust dose and time-dependent hyperacetylation in the 3-NPA model. Chromatin Immunoprecipitation-sequencing (ChIP-seq) revealed that acetylated H3K56 was associated with 13072 chromatin sites, which showed increased occupancy in the transcription start site-promoter site. Acetylated histone H3K56 was associated with 1747 up-regulated and 263 down-regulated genes in the 3-NPA model, which included many up-regulated autophagy and mitophagy genes. Western analysis validated the involvement of PINK1-Parkin dependent mitophagy in the 3-NPA model. We propose that 3-NPA specific chromatin dynamics could contribute to the unique transcriptomic profile with implications for movement disorders.
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PMID:Exposure to the neurotoxin 3-nitropropionic acid in neuronal cells induces unique histone acetylation pattern: Implications for neurodegeneration. 3292 24