Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

beta-N-oxalyl-amino-L-alanine, (L-BOAA), an excitatory amino acid, acts as an agonist of the AMPA subtype of glutamate receptors. It inhibits mitochondrial complex I in motor cortex and lumbosacral cord of male mice through oxidation of critical thiol groups, and glutaredoxin, a thiol disulfide oxido-reductase, helps maintain integrity of complex I. Since incidence of neurolathyrism is less common in women, we examined the mechanisms underlying the gender-related effects. Inhibition of complex I activity by L-BOAA was seen in male but not female mice. Pretreatment of female mice with estrogen receptor antagonist ICI 182,780 or tamoxifen sensitizes them to L-BOAA toxicity, indicating that the neuroprotection is mediated by estrogen receptors. L-BOAA triggers glutathione (GSH) loss in male mice but not in female mice, and only a small but significant increase in oxidized glutathione (GSSG) was seen in females. As a consequence, up-regulation of gamma-glutamyl cysteinyl synthase (the rate-limiting enzyme in glutathione synthesis) was seen only in male mouse CNS but not in females. Both glutathione reductase and glutaredoxin that reduce oxidized glutathione and protein glutathione mixed disulfides, respectively, were constitutively expressed at higher levels in females. Furthermore, glutaredoxin activity in female mice was down-regulated by estrogen antagonist indicating its regulation by estrogen receptor. The higher constitutive expression of glutathione reductase and glutaredoxin could potentially confer neuroprotection to female mice.
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PMID:Down-regulation of glutaredoxin by estrogen receptor antagonist renders female mice susceptible to excitatory amino acid mediated complex I inhibition in CNS. 1710 34

Oxidative stress and protein aggregation are biochemical hallmarks of Parkinson's disease (PD), a frequent sporadic late-onset degenerative disorder particularly of dopaminergic neurons in the substantia nigra, resulting in impaired spontaneous movement. PARK6 is a rare autosomal-recessively inherited disorder, mimicking the clinical picture of PD with earlier onset and slower progression. Genetic data demonstrated PARK6 to be caused by mutations in the protein PINK1, which is localized to mitochondria and has a serine-threonine kinase domain. To study the effect of PINK1 mutations on oxidative stress, we used primary fibroblasts and immortalized lymphoblasts from three patients homozygous for G309D-PINK1. Oxidative stress was evident from increases in lipid peroxidation and in antioxidant defenses by mitochondrial superoxide dismutase and glutathione. Elevated levels of glutathione reductase and glutathione-S-transferase were also observed. As a putative cause of oxidation, a mild decrease in complex I activity and a trend to superoxide elevation were detectable. These data indicate that PINK1 function is critical to prevent oxidative damage and that peripheral cells may be useful for studies of progression and therapy of PARK6.
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PMID:Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. 1714 10

The mechanism of retinal ganglion cell loss in Leber's hereditary optic neuropathy (LHON) is still uncertain, and a role of enhanced superoxide production by the mutant mitochondrial complex I has been hypothesized. In the present study, it was shown that LHON cybrids, carrying the np11778 mutation, became selectively more H(2)O(2) sensitive compared with the parental cell line only following short-term retinoic acid differentiation. They contained a decreased cellular glutathione pool (49%, p< or =0.05), despite 1.5-fold enhanced expression of the regulatory subunit of gamma-glutamylcysteine synthetase (p< or =0.05). This points to a reduction of the capacity to detoxify H(2)O(2) and to changes in thiol redox potential. The activity of the H(2)O(2) degrading enzyme glutathione peroxidase (GPx) and the activities of glutathione reductase (GR) and superoxide dismutase (SOD) were unaffected.
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PMID:Glutathione depletion in antioxidant defense of differentiated NT2-LHON cybrids. 1716 68

The modulatory efficacy of capsaicin on lung mitochondrial enzyme system with reference to mitochondrial lipid peroxidation (LPO), antioxidants, key citric acid cycle enzymes and respiratory chain enzymes during benzo(a)pyrene (B(a)P) induced lung cancer in Swiss albino mice was studied. Elevations in mitochondrial LPO along with decrements in enzymic antioxidants (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST)), non-enzymic antioxidants (reduced glutathione (GSH), vitamin C, vitamin E and vitamin A), citric acid cycle enzymes (isocitrate dehydrogenase (ICDH), alpha-ketoglutarate dehydrogenase (alpha-KDH), succinate dehydrogenase (SDH) and malate dehydrogenase (MDH)), and respiratory chain enzymes (NADH dehydrogenase and Cytochrome c oxidase) were observed in B(a)P (50mg/kg body weight) administered animals. CAP (10mg/kg body weight) pretreatment decreased lung mitochondrial LPO and augmented the activities of enzymic, non-enzymic antioxidants, citric acid cycle enzymes and respiratory chain enzymes to near normalcy revealing its chemoprotective function during B(a)P induced lung cancer.
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PMID:Stabilization of pulmonary mitochondrial enzyme system by capsaicin during benzo(a)pyrene induced experimental lung cancer. 1802 35

The protein complexes of pea (Pisum sativum L.) etioplasts, etio-chloroplasts and chloroplasts were examined using 2D Blue Native/SDS-PAGE. The most prominent protein complexes in etioplasts were the ATPase and the Clp and FtsH protease complexes which probably have a crucial role in the biogenesis of etioplasts and chloroplasts. Also the cytochrome b(6)f (Cyt b(6)f) complex was assembled in the etioplast membrane, as well as Rubisco, at least partially, in the stroma. These complexes are composed of proteins encoded by both the plastid and nuclear genomes, indicating that a functional cross-talk exists between pea etioplasts and the nucleus. In contrast, the proteins and protein complexes that bind chlorophyll, with the PetD subunit and the entire Cyt b(6)f complex as an exception, did not accumulate in etioplasts. Nevertheless, some PSII core components such as PsbE and the luminal oxygen-evolvong complex (OEC) proteins PsbO and PsbP accumulated efficiently in etioplasts. After 6 h de-etiolation, a complete PSII core complex appeared with 40% of the maximal photochemical efficiency, but a fully functional PSII was recorded only after 24 h illumination. Similarly, the core complex of PSI was assembled after 6 h illumination, whereas the PSI-light-harvesting complex I was stably assembled only in chloroplasts illuminated for 24 h. Moreover, a battery of proteins responsible for defense against oxidative stress accumulated particularly in etioplasts, including the stromal and thylakoidal forms of ascorbate peroxidase, glutathione reductase and PsbS.
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PMID:Expression of protein complexes and individual proteins upon transition of etioplasts to chloroplasts in pea (Pisum sativum). 1826 21

The mechanism of free radical production by complex I deficiency is ill-defined, although it is of significant contemporary interest. This study studied the ROS production and antioxidant defenses in children with mitochondrial NADH dehydrogenase deficiency. ROS production has remained significantly elevated in patients compared to controls. The expression of all antioxidant enzymes significantly increased at mRNA level. However, the enzyme activities did not correlate with high mRNA or protein expression. Only the activity of superoxide dismutase (SOD) was found to correlate with higher mRNA expression in patient derived cell lines. The activities of the enzymes such as glutathione peroxidase (GPx), Catalase (CAT) and glutathione-S-transferase (GST) were significantly reduced in patients (p<0.05 or p<0.01). Glutathione reductase (GR) activity and intracellular glutathione (GSH) levels were not changed. Decreased enzyme activities could be due to post-translational or oxidative modification of ROS scavenging enzymes. The information on the status of ROS and marking the alteration of ROS scavenging enzymes in peripheral lymphocytes or lymphoblast cell lines will provide a better way to design antioxidant therapies for such disorders.
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PMID:Analysis of reactive oxygen species and antioxidant defenses in complex I deficient patients revealed a specific increase in superoxide dismutase activity. 1855 9

The present study investigates the effect of aspartate and glutamate on mitochondrial function during myocardial infarction (MI) in wistar rats. Male albino wistar rats were pretreated with aspartate [100 mg(kgbody weight)(-1) day(-1)] or glutamate [100 mg(kg body weight)(-1) day(-1)] intraperitoneally for a period of 7 days. Following amino acid treatment, MI was induced in rats by subcutaneous injection of isoproterenol [200 mg(kg body weight)(-1) day(-1)] for 2 days at an interval of 24 h. Isoproterenol (ISO) induction resulting in significant (P<0.05) increase in the levels of cardiac mitochondrial lipid peroxidation with a decrease in reduced glutathione level. The activities of glutathione peroxidase and glutathione reductase were significantly (P<0.05) decreased by ISO. ISO-induction also caused significant (P<0.05) decrease in the activities of mitochondrial tricarboxylic acid cycle enzymes (malate dehydrogenase, isocitrate dehydrogenase, succinate dehydrogenase, alpha-ketoglutarate dehydrogenase) and respiratory chain enzymes (NADH dehydrogenase and cytochrome-c-oxidase). ISO significantly (P<0.05) reduced the cytochrome contents, ATP production, ADP/O ratio and oxidation of succinate in state 3/state 4 whereas significantly (P<0.05) increased NADH oxidation. Pretreatment with aspartate or glutamate significantly (P<0.05) reduced the alterations induced by ISO and maintained normal mitochondrial function. The present findings reveal the protective effect of aspartate and glutamate on cardiac mitochondrial function in myocardial infarction-induced rats.
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PMID:Protective effect of aspartate and glutamate on cardiac mitochondrial function during myocardial infarction in experimental rats. 1878 22

We purified an NADPH-dependent coenzyme Q reductase (NADPH-CoQ reductase) in rat liver cytosol and compared its enzymatic properties with those of the other CoQ10 reductases such as NADPH: quinone acceptor oxidoreductase 1 (NQO1), lipoamide dehydrogenase, thioredoxine reductase and glutathione reductase. NADPH-CoQ reductase was the only enzyme that preferred NADPH to NADH as an electron donor and was also different from the other CoQ10 reductases in the sensitivities to its inhibitors and stimulators. Especially, Zn2+ was the most powerful inhibitor for NADPH-CoQ reductase, but CoQ10 reduction by the other CoQ10 reductases could not be inhibited by Zn2+. Furthermore, the reduction of the CoQ9 incorporated into HeLa cells was also inhibited by Zn2+ in the presence of pyrithione, a zinc ionophore. Moreover, NQO1 gene silencing in HeLa cells by transfection of a small interfering RNA resulted in lowering of both the NQO1 protein level and the NQO1 activity by about 75%. However, this transfection did not affect the NADPH-CoQ reductase activity and the reduction of CoQ9 incorporated into the cells. These results suggest that the NADPH-CoQ reductase located in cytosol may be the main enzyme responsible for the reduction of non-mitochondrial CoQ in cells.
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PMID:NADPH-dependent coenzyme Q reductase is the main enzyme responsible for the reduction of non-mitochondrial CoQ in cells. 1909 1

Incidence of Parkinson's disease (PD) is lower in women compared to men (1:1.46), which is reflected in animal models. However, precise mechanisms are unclear. Administration of MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) to female mice does not lead to mitochondrial complex I inhibition as seen in males and the progressive dopaminergic cell loss in substantia nigra (SNpc) is significantly attenuated. Redox driven apoptotic signaling pathways regulated by thiol disulfide oxidoreductase(s) have been implicated in the neurodegeneration seen in PD. Oxidation of thioredoxin leads to activation of apoptosis signal regulating kinase 1 (ASK1; MAPKKK) initiating cell death cascade through MAP kinase(s). Higher constitutive expression of enzymes involved in cellular redox maintenance, such as glutathione reductase, thioredoxin, and thioredoxin reductase is observed in female brain. Exposure to MPTP activates ASK1 in male but not in female mice. Higher expression of Trx in females potentially prevents ASK1 activation. Downstream of ASK1, phosphorylation of p38 MAP kinase is seen in male but not female mice. Expression of DJ-1, the redox sensing protein is higher in females and the loss of nuclear DJ-1, followed by translocation of Daxx (death associated protein) from the nucleus to the cytosol, which promotes ASK1 mediated death cascade is not seen in females. The enzymes involved in redox maintenance potentially could play a crucial role in preventing the activation of redox driven death signaling cascade and offer neuroprotection. Theraupeutic strategies that help maintain redox homeostasis may help prevent the progressive neurodegeneration seen in PD.
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PMID:Redox activated MAP kinase death signaling cascade initiated by ASK1 is not activated in female mice following MPTP: novel mechanism of neuroprotection. 1952 88

Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Reactive oxygen species (ROS) are crucial to Ca(2+)-mediated effects of glutamate receptor activation leading to neuronal degeneration. Tetramethylpyrazine (TMP) is a principal ingredient of Ligusticum wallichi Franchat (a Chinese herb), used for treatment of cardiovascular and cerebrovascular ischemic diseases. However, its protection against oxidative brain injury associated with excessive activation of glutamate receptors is unknown. In this study, we demonstrate TMP neuroprotection against kainate-induced excitotoxicity in vitro and in vivo. We found that TMP could partly alleviate kainate-induced status epilepticus in rats and prevented and rescued neuronal loss in the hippocampal CA3 but not the CA1 region. The partial prevention and rescue of neuronal loss by TMP were attributable to the preservation of the structural and functional integrity of mitochondria, evidenced by maintaining the mitochondrial membrane potential, ATP production, and complex I and III activities. Stabilization of mitochondrial function was linked to the observation that TMP could function as a reductant/antioxidant to quench ROS, block lipid peroxidation, and protect enzymatic antioxidants such as glutathione peroxidase and glutathione reductase. These results suggest that TMP may protect against oxidative brain injury by stabilization of mitochondrial function through quenching of ROS.
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PMID:Stabilization of mitochondrial function by tetramethylpyrazine protects against kainate-induced oxidative lesions in the rat hippocampus. 2000 2


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