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)

To investigate the molecular abnormality in the mitochondria from various tissues of an autopsied patient exhibiting mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, we have examined the enzymatic activity, iron-sulfur cluster, and subunit composition of the NADH-ubiquinone oxidoreductase (complex I). Rotenone-sensitive NADH-cytochrome c reductase activity was found to be decreased in all the tissues examined. A detailed study of the liver mitochondria has shown that NADH-ubiquinone oxidoreductase activity was greatly diminished. Analysis of the electron paramagnetic resonance spectra of the liver submitochondrial particles revealed a disproportionate deficiency of iron-sulfur clusters in the complex I segment of the respiratory chain. Signals from the clusters N-2 and N-3 diminished more drastically than those from clusters N-1b and N-4. Immunoblotting analysis showed that the 75-kD, 51-kD, and several other subunits were markedly diminished among multiple subunit polypeptides of complex I. These findings suggest that the underlying bases for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes are defects, at least, in the complex I subunits containing a flavin and/or iron-sulfur cluster(s), which resulted in deficiencies of some iron-sulfur clusters.
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PMID:Disproportionate deficiency of iron-sulfur clusters and subunits of complex I in mitochondrial encephalomyopathy. 249 47

Incubation of chromate with isolated rat liver submitochondrial particles under anaerobic conditions in vitro results in reduction of chromium(VI) and formation of chromium(V). In the presence of NADH, submitochondrial particles (SMPs) were active in reducing chromate as shown by UV-vis spectroscopic studies, and forming a chromium(V) species which was detectable by electron paramagnetic resonance spectroscopy. In the presence of succinate, SMPs were less effective in reducing chromate and forming chromium(V) relative to their NADH-dependent activity. However, SMPs showed a higher rate of oxygen depletion with NADH as compared to succinate as substrate, suggesting that differences in the NADH-dependent versus succinate-dependent chromate-reductase activity of SMPs is probably due to differences in efficiency of electron donation by succinate and NADH. The use of specific electron transport chain inhibitors allowed the sites of chromium(VI) reduction and chromium(V) formation in SMPs to be determined. Rotenone, antimycin and cyanide all produced approximately 40% inhibition of the NADH-dependent chromate-reductase activity. Thus, complex I (NADH:ubiquinone oxidoreductase) appears to be responsible for the inhibitor-insensitive, and complex IV (ferrocytochrome c:oxygen oxidoreductase) for the inhibitor-sensitive NADH-dependent chromium(VI) reduction and chromium(V) formation. Cyanide and antimycin produced approximately 50% inhibition of the succinate-dependent chromate-reductase activity of SMPs, while no detectable inhibition was observed with rotenone. These results confirm the chromate-reductase activity of complex IV, and suggest that complex II (succinate:ubiquinone oxidoreductase) is responsible for the inhibitor-insensitive succinate-dependent chromate-reductase activity of SMPs. Since chromium(VI) is effectively metabolized by electron transport chain complexes of the mitochondrial inner membrane in vitro, and chromium(V) is formed as an intermediate in the process, mitochondria may play a role in chromium(VI) carcinogenesis.
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PMID:Chromium(V) is produced upon reduction of chromate by mitochondrial electron transport chain complexes. 253 17

Rotenone-sensitive NADH dehydrogenase activity and Lubrol stimulation of cytochrome oxidase activity were measured to assess the opposite membrane polarity of beef heart mitoplast and inside-out particle preparations. The ATP-Pi exchange activity of mitoplasts was not affected by their incubation at pH 8.9 in the presence of 5 mM EDTA (a treatment known to extract coupling factor B (F beta) from submitochondrial particles), nor was it stimulated by the addition of F beta to intact and alkaline treated mitoplast preparations. In contrast, the exchange activity of inside-out particles was decreased 18 fold by the alkaline/EDTA treatment and was almost completely restored by the addition of F beta to F beta-depleted particles. From these results it is concluded that in beef heart mitochondria, the coupling factor F beta is bound to the matrix-side of the inner mitochondrial membrane.
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PMID:Evidence that coupling factor B is bound to the matrix side of the inner mitochondrial membrane. 256 42

Esters of carboxylic acids are permeable to cells and once inside the cell are hydrolyzed to carboxylic acids. Methyl and ethyl esters of succinate and other citric acid cycle intermediates were tested to find out whether they are insulin secretagogues. Monomethyl succinate stimulated insulin release from pancreatic islets in a concentration-dependent manner with maximal release attained at a concentration of 10 mM. Dimethyl succinate (10 mM) was as effective as monomethyl succinate, but pyruvate methyl ester, monoethyl succinate, and dimethyl fumarate were ineffective as primary secretagogues. However, dimethyl fumarate potentiated both leucine- and leucine-plus-glutamine-induced insulin release. Glucose, leucine, leucine plus glutamine, and monomethyl succinate increased inositol tris-, bis- and monophosphate formation in pancreatic islets and antimycin A inhibited this formation. Since mitochondrial metabolism is probably essential for glucose-induced insulin release and the metabolism of succinate and leucine (without or with glutamine) involves mitochondrial respiration exclusively, these results might indicate that mitochondrial metabolism generates conditions or factors that are transmitted to the cytosol to increase inositol trisphosphate formation and thus calcium mobilization and insulin release. Since succinate is believed to enter metabolism at site II of the mitochondrial respiratory chain, it is interesting that rotenone, an inhibitor of NADH dehydrogenase and site I of the respiratory chain, was a potent inhibitor of monomethyl succinate-induced insulin released. Rotenone also inhibited leucine (plus or minus glutamine)-induced insulin release. These results indicate that beta cell metabolism of monomethyl succinate and leucine, like glucose, influences dehydrogenases that produce NADH.
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PMID:Effect of esters of succinic acid and other citric acid cycle intermediates on insulin release and inositol phosphate formation by pancreatic islets. 264 27

Muscle biopsy specimens from two patients with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) were studied biochemically. 14CO2 production rates from (1-14C)pyruvate, (U-14C)malate, and (1-14C)2-ketoglutarate were all decreased in intact mitochondria in both patients. Rotenone-sensitive NADH cytochrome c reductase activities were decreased to 8% (patient 1) and 6% (patient 2) of control values; succinate cytochrome c reductase and cytochrome c oxidase values were within normal limits. These results indicate that both patients have a defect of NADH-CoQ reductase of the respiratory chain and that MELAS can be brought about by a defect of NADH-CoQ reductase.
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PMID:Two cases of NADH-coenzyme Q reductase deficiency: relationship to MELAS syndrome. 310 Jul 53

Enzymic activity and the levels of immunochemically detectable subunits of NADH-ubiquinone oxidoreductase (Complex I) were measured in the mitochondria from various tissues of a patient with mitochondrial encephalomyopathy and renal dysfunction. Rotenone-sensitive NADH-cytochrome c reductase activity was decreased in all the tissues examined, but the degree of deficiency varied from tissue to tissue. The levels of subunits in Complex I were decreased roughly in parallel with the activity in each tissue. These results indicate that the apparently tissue-specific manifestation of symptoms depends mainly on the levels of subunits in Complex I.
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PMID:Variation in the levels of complex I subunits among tissues in a patient with mitochondrial encephalomyopathy and renal dysfunction. 313 26

The respiratory chain-linked external NADH dehydrogenase has been isolated from Candida utilis in highly purified form. The enzyme is soluble and has a molecular weight of approx. 1.5 x 10(6). The enzyme contains two moles of FMN per mole of enzyme and is composed of two large subunits of mol. wt. 270 000 and eight smaller subunits of mol. wt. 135 000. Iron and copper are present in the preparations, but appear to be contaminants. The enzyme catalyzes the oxidation of NADH and NADPH at nearly equal rates and reacts readily with 2,6-dichlorophenolindophenol, CoQ6 and CoQ1 derivatives as acceptors. Rotenone (10(-5) M) and seconal (10(-3) M) do not inhibit enzymatic activity.
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PMID:Electron transport systems of Candida utilis: purification and properties of the respiratory chain-linked external NADH dehydrogenase. 719 Apr 38

The role of complex II in the cellular protection against oxidative stress was investigated in freshly isolated rat renal proximal tubular cells (PTC) with the use of the nephrotoxin S-(1,2-dichlorovinyl)-L-cysteine (DCVC). DCVC caused oxidative stress in PTC as determined by flow cytometry with dihydrorhodamine-123; this fluorescent probe is readily oxidized by primary hydroperoxides such as those formed during lipid peroxidation. The oxidative stress could be prevented by inhibition of the beta-lyase-mediated formation and covalent binding to cellular macromolecules of reactive DCVC metabolites, with amino oxyacetic acid (AOA), or by the antioxidant N,N'-diphenyl-p-phenylenediamine. Both AOA and DPPD also prevented cell death. The DCVC-induced oxidative stress was associated with a decrease in the succinate:ubiquinone reductase (SQR) activity of complex II, whereas NADH:ubiquinone reductase activity of complex I remained unaffected. AOA prevented the effect on SQR activity, whereas N,N'-diphenyl-p-phenylenediamine did not. Inhibition of SQR activity with thenoyl trifluoracetone (TTFA) potentiated the DCVC-induced oxidative cell injury, suggesting the involvement of SQR activity in an antioxidant pathway. To investigate this in greater detail, PTC were treated with an inhibitor of cytochrome-c-oxidase, KCN, in a buffer containing glycine, which prevents cell death by KCN. Glycine did not affect cell death by DCVC. KCN prevented the DCVC-induced oxidative stress and cell death. KCN cytoprotection could be prevented by inhibition of SQR activity with oxaloacetate or TTFA, whereas inhibition of either complex I or III with rotenone and antimycin, respectively, did not prevent it. The effect of DCVC on complex II was associated with a decrease in the cellular amount of reduced ubiquinone (QH2); the KCN-mediated cytoprotection was related to a 60% increase of cellular QH2. Rotenone almost completely inhibited ubiquinone reduction even in the presence of KCN, whereas oxaloacetate in combination with KCN resulted in QH2 levels comparable to control. This suggests that the SQR activity by complex II rather than the cellular content of reduced ubiquinone (QH2) is important as a part of the cellular antioxidant machinery in the cyto-protection against oxidative stress.
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PMID:Inhibition of succinate:ubiquinone reductase and decrease of ubiquinol in nephrotoxic cysteine S-conjugate-induced oxidative cell injury. 747 24

The rate of transfer of reducing equivalents from cytoplasm to mitochondria has been examined in Ehrlich ascites tumour cells incubated in the presence of lactate. The flux of reducing equivalents was determined from the rate of metabolism of reduced intermediates that are oxidized within the cytosol. The magnitude of the flux of reducing equivalents was dependent on both the concentration of added lactate and the presence of carbohydrate. The rate of flux was twice as great in the presence of glucose and four times as high when glucose and lactate were added together as when lactate was the only added substrate. Fructose was less effective than glucose in stimulating reducing equivalent flux. In the presence of glucose or fructose, there was a substantial accumulation of hexose phosphates, dihydroxyacetone phosphate and glycerol 3-phosphate. Rotenone, an inhibitor of NADH dehydrogenase, and amino-oxyacetate, which inhibits the malate/aspartate shuttle, were powerful suppressors of reducing equivalent flux from lactate as sole substrate, but were much less potent in the presence of carbohydrate. Antimycin substantially inhibited reducing equivalent flux from all combinations of added substrates, consistent with its ability to block oxidation of reducing equivalents transferred by both the malate/aspartate and glycerol 3-phosphate shuttles. The glycerol 3-phosphate shuttle represents around 80% of the maximum total observed activity but is active only while glycolytic intermediates are present to provide the necessary substrates of the shuttle. This Ehrlich ascites cell line has an essentially similar total reducing equivalent shuttle capacity to that of isolated hepatocytes.
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PMID:Substrate-dependent utilization of the glycerol 3-phosphate or malate/aspartate redox shuttles by Ehrlich ascites cells. 765 9

Recent studies suggest that defects in the function of the complexes of the electron transport chain might be involved in the pathology of neurological diseases such as mitochondrial encephalopathies, Parkinson's, Huntington's and Alzheimer's disease. Rotenone is a potent reversible competitive inhibitor of complex I (NADH-CoQ reductase). To study the possible involvement of complex I in such diseases, we synthesized (2-[11C]methoxy)rotenone by [11C]alkylation of 2-O-desmethyl rotenone methyl enol ether followed by hydrolysis of the enol ether to the ketone using aqueous trifluoroacetic acid. (2-[11C]Methoxy)rotenone was purified by high pressure liquid chromatography (silica gel) and was obtained in 7-10% yields decay corrected to end of bombardment in synthesis times typically shorter than 48 min. Radiochemical purities were over 95% and specific activities averaged 1000 Ci/mmol at end of synthesis.
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PMID:Synthesis of (2-[11C]methoxy)rotenone, a marker of mitochondrial complex I activity. 773 72


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