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)

A mitochondrial extract from Leishmania tarentolae directs the incorporation of uridylate (U) residues within the pre-edited domain of synthetic cytochrome b (CYb) and NADH dehydrogenase subunit 7 mRNA. This has several characteristics of an in vitro RNA editing activity, but no direct evidence for involvement of guide RNAs was obtained. Inhibition by micrococcal nuclease suggests a requirement for some type of endogenous RNA. The limitation of internal U-incorporation to the pre-edited region in the CYb mRNA and the inhibition by deletion or substitution of both mRNA anchor sequences for CYb gRNA-I and -II could be consistent either with a gRNA-mediated process or a secondary structure-mediated process. A low level of incorporation of [alpha-32P]CTP occurs at the same sites as UTP. Internal U-incorporation activity is selectively inhibited by heterologous RNAs, suggesting an involvement of low affinity RNA-binding proteins which can be competed by the added RNA.
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PMID:In vitro RNA editing-like activity in a mitochondrial extract from Leishmania tarentolae. 782 90

A mutant strain of D. Subobscura possesses two populations of mitochondrial genomes: a population identical to that of the wild strain (20%) and a dominant population (80%) which has lost more than 30% of its coding zone by deletion. Spectrophotometric determination of respiratory complex activities shows that: complex I (5 genes implicated in deletion) presents maximal activity reduced by 40%, whereas that of complex III (concerned by cytochrome b) is lowered by 30%. Nevertheless, polarographic determinations of substrate oxidation show activity of complex I to be reduced by 30%. In contrast, complex III activity is similar to that measured in the wild strain. The predominant use of one part of the respiratory chain may account for the fact that the mutant strain is apparently unaffected by mutation.
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PMID:Biochemical consequences of a large deletion in the mitochondrial genome of a Drosophila subobscura strain. 821 12

We have sequenced a segment of mitochondrial DNA (mtDNA) of a crustacean, the brine shrimp, Artemia salina, that includes 3' end-proximal regions of the genes for subunit 1 of the NADH dehydrogenase complex (ND1) and cytochrome b (Cyt b). From our data we conclude that in this mtDNA, as in the mtDNAs of Drosophila species, a tRNA(Ser)(UCN) gene separates the ND1 and Cyt b genes. This is contrary to an earlier report that the A. salina ND1 and Cyt b genes are immediately adjacent to each other.
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PMID:A tRNA(Ser)(UCN) gene in Artemia salina mitochondrial DNA: a case of mistaken identity. 825 41

Pearson's syndrome, a rare and fatal disorder characterized by refractory sideroblastic anemia and pancreatic insufficiency in infancy, is classified into mitochondrial cytopathies. To understand the molecular and genetic bases of this disorder, we have investigated the mitochondrial respiratory chain enzymes and the mitochondrial DNA (mtDNA) in two Japanese patients with Pearson's syndrome. Immunoblot analysis from various tissues showed the different grades of defects in the subunits of respiratory enzyme complexes. The analyses of mtDNA showed that the deletion in patient 1 spanned 4977 bp from the ATPase 8 gene to the NADH dehydrogenase 5 gene between 13-bp direct repeats, whereas the deletion in patient 2 spanned 3151 bp from the transfer RNA(His) gene to the cytochrome b gene unrelated to any repeated sequences. The deleted mtDNA was heteroplasmic in all the analyzed tissues, but the proportions of deleted mtDNA were quite different. We observed a tendency for the tissue with low percentages of normal-sized mtDNA to show low contents of complex I subunits. Analysis of the entire sequence of both patient's mtDNA showed several nucleotide substitutions including alteration of the initiation codon of the NADH dehydrogenase 5 gene. Some of these nucleotide substitutions might contribute to the phenotypic expression of Pearson's syndrome synergistically with the deletion.
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PMID:Molecular and genetic analyses of two patients with Pearson's marrow-pancreas syndrome. 835 10

The objective of this study was to explore the possible cause(s) underlying the previously observed, age-related increase in the rate of mitochondrial H2O2 release in the housefly. The hypothesis that an imbalance between different respiratory complexes may be a causal factor was tested. Cytochrome c oxidase activity was found to sharply decline in the latter part of the life span of the flies. Effects of different substrates and respiratory inhibitors were determined in order to ascertain if a decrease in cytochrome c oxidase activity could be responsible for the increased H2O2 release. H2O2 was measured spectrofluorometrically using horseradish peroxidase and p-hydroxphenylacetate as an indicator. Neither NADH-linked substrates nor succinate caused a stimulation of H2O2 production. H2O2 release by mitochondria, inhibited with rotenone and antimycin A, was greatly increased upon supplementation with alpha-glycerophosphate; however, the further addition of KCN or myxothiazol, to such preparations, caused a depression of H2O2 generation. In contrast, relatively low concentrations of KCN or myxothiazol were found to stimulate H2O2 release in insect mitochondria supplemented with alpha-glycerophosphate and exposed to rotenone, but not antimycin A. Results are interpreted to suggest that partial inhibition of cytochrome c oxidase activity can lead to the stimulation of mitochondrial H2O2 production in the housefly at site(s) other than NADH dehydrogenase and ubisemiquinone/cytochrome b region; a possible source may be glycerophosphate dehydrogenase.
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PMID:Aging, cytochrome oxidase activity, and hydrogen peroxide release by mitochondria. 839 19

We characterized six novel missense mutations in mitochondrial cytochrome b (C133Y, W142R, S206L, M221K, L282F, and G340E) which impair the respiratory growth of yeast and which have differential effects on the functioning and assembly of the bc1 complex. The mutations have been mapped genetically in exons of the mitochondrial gene coding for apocytochrome b and their nucleotide sequence established. The mutants help to better define the topographical and primary sequence location of the ubiquinol oxidase (center P) and ubiquinone reductase (center N) sites on cytochrome b. Two mutants (C133Y and S206L) resulted in an active assembled complex, with selective disturbances of heme 565 and heme 562, respectively, which is consistent with the assignment of the axial ligands of these hemes; the C133Y mutation induced myxothiazol resistance, whereas the S206L did not modify the antimycin binding site, although perturbing the center N. These two amino acid replacements, along with those described elsewhere (Tron, T., and Lemesle-Meunier, D. (1990) Curr. Genet. 18, 413-419), constitute a novel class of mutants exhibiting appreciable electron transfer activity, despite their impaired ability to grow on respiratory substrates, raising the possibility that these mutants carry alleles which result in "decoupling" of proton translocation from electron transfer. Mutants W142R and M221K had an inactive but well assembled bc1 complex, whereas the G34OE and L282F mutations impaired the assembly of the bc1 complex.
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PMID:Cytochrome b-deficient mutants of the ubiquinol-cytochrome c oxidoreductase in Saccharomyces cerevisiae. Consequence for the functional and structural characteristics of the complex. 839 50

A simple system for aerobic assay of the quinol-fumarate reductase reaction catalyzed by purified soluble bovine heart succinate-ubiquinone reductase in the presence of NADH, NAD(P)H-quinone reductase (DT-diaphorase) and an appropriate quinone is described. The reaction is inhibited by carboxin, suggesting that the same quinone/quinol binding site is involved in electron transfer from succinate to ubiquinone and from ubiquinol to fumarate. The kinetic properties of the reaction in both directions and comparative affinities of the substrate binding sites of the enzyme to substrates (products) and competitive inhibitors are reported. Considerable difference in affinity of the substrates binding site to oxaloacetate was demonstrated when the enzyme was assayed in the direct and reverse directions. These results were taken to indicate that the oxidized dicarboxylate-free enzyme is an intermediate during the steady-state succinate-ubiquinone reductase reaction, whereas the reduced dicarboxylate-free enzyme is an intermediate of the steady-state ubiquinol-fumarate reductase reaction. No difference in the reactivity of the substrate-protected cysteine and arginine residues was found when the pseudo-first-order rate constants for N-ethylmaleimide and phenylglyoxal inhibition were determined for oxidized and quinol-reduced enzyme. Quinol-fumarate reductase activity was reconstituted from the soluble succinate dehydrogenase and low-molecular-mass ubiquinone reactivity conferring protein(s). No reduction of cytochrome b was observed in the presence of quinol generating system, whereas S-3 low temperature EPR-detectable iron-sulfur center was completely reduced by quinol under equilibrium (without fumarate) or steady-state (in the presence of fumarate). No significant reduction of ferredoxin type iron-sulfur centers was detected during the steady-state quinol-fumarate oxidoreductase reaction. The data obtained eliminate participation of cytochrome b in the quinol-fumarate reductase reaction and show that the rate limiting step of the overall reaction lies between iron-sulfur center S-3 and lower midpoint potential redox components of the enzyme.
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PMID:Fumarate reductase activity of bovine heart succinate-ubiquinone reductase. New assay system and overall properties of the reaction. 841 79

Studies were undertaken to investigate the principal actions underlying mercury-induced oxidative stress in the kidney. Mitochondria from kidneys of rats treated with HgCl2 (1.5 mg/kg i.p.) demonstrated a 2-fold increase in hydrogen peroxide (H2O2) formation for up to 6 hr following Hg(II) treatment using succinate as the electron transport chain substrate. No increase in H2O2 formation was observed when NAD-linked substrates (malate/glutamate) were used, suggesting that Hg(II) affects H2O2 formation principally at the ubiquinone-cytochrome b region of the mitochondrial respiratory chain in vivo. Together with increased H2O2 formation, mitochondrial glutathione (GSH) content was depleted by more than 50% following Hg(II) treatment, whereas formation of thiobarbiturate reactive substances (TBARS), indicative of mitochondrial lipid peroxidation, was increased by 68%. Studies in vivo revealed a significant concentration-related depolarization of the inner mitochondrial membrane following the addition of Hg(II) to mitochondria isolated from kidneys of untreated rats. This effect was accompanied by significantly increased H2O2 formation, GSH depletion and TBARS formation linked to both NADH dehydrogenase (rotenone-inhibited) and ubiquinone-cytochrome b (antimycin-inhibited) regions of the electron transport chain. Oxidation of pyridine nucleotides (NAD[P]H) was also observed in mitochondria incubated with Hg(II) in vitro. In further studies in vitro, the potential role of Ca2+ in Hg(II)-induced mitochondrial oxidative stress was investigated. Ca2+ alone (30-400 nmol/mg protein) produced no increase in H2O2 and only a slight increase in TBARS formation when incubated with kidney mitochondria isolated from untreated rats. However, Ca2+ significantly increased H2O2 and TBARS formation elicited by Hg(II) at the ubiquinone-cytochrome b region of the mitochondrial electron transport chain, whereas TBARS formation was decreased significantly when the Ca2+ uptake inhibitors, ruthenium red or [ethylenebis(oxyethylenenitrilo)]tetraacetic acid (EGTA), were included with Hg(II) in the reaction mixtures. These findings support the view that Hg(II) causes depolarization of the mitochondrial inner membrane with consequent increased H2O2 formation. These events, coupled with Hg(II)-mediated GSH depletion and pyridine nucleotide oxidation, create an oxidant stress condition characterized by increased susceptibility of mitochondrial membranes to iron-dependent lipid peroxidation (TBARS formation). Since increased H2O2 formation, GSH depletion and lipid peroxidation were also observed in vivo following Hg(II) treatment, these events may underlie oxidative tissue damage caused by mercury compounds. Moreover, Hg(II)-induced alterations in mitochondrial Ca2+ homeostasis may exacerbate Hg(II)-induced oxidative stress in kidney cells.
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PMID:Studies on Hg(II)-induced H2O2 formation and oxidative stress in vivo and in vitro in rat kidney mitochondria. 851 85

4(1H)-quinolones (2-alkyl- (1), 2-alkyl-3-methyl- (2), 2-methyl-3-alkyl- (3), 1-hydroxy-2-methyl-3-alkyl- (4) and 1-hydroxy-2-alkyl- (5)) with n-alkyl side chains varying from C5 to C17 have been synthesized and tested for biological activity in mitochondrial complexes. Whereas all quinolones were efficient inhibitors of electron transport in the cytochrome b/c1-complex from either beef heart or Rhodospirillum rubrum, in complex I from beef heart quinolones 1 and 2 only were highly active. In a Quantitative Structure-Activity Relationship (QSAR) inhibitory activity in the cytochrome b/c1-complexes could be correlated to the physicochemical parameters lipophilicity pi and/or to STERIMOL L. Maximal inhibitory potency was achieved at a carbon chain length of 12-14 A. Oxidant-induced reduction of cytochrome b established that some quinolones are inhibitors of the Qp rather than the Qn site.
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PMID:Quinolones and their N-oxides as inhibitors of mitochondrial complexes I and III. 903 Feb 70

We examined effects of several compounds, structurally related to 1-methyl-4-phenylpyridinium (MPP+), on the NADH-dependent respiration of bovine heart submitochondrial particles. 1-Methyl-4-(3 '-trimethylammoniophenyl)pyridinium (analog 8) as well as MPP+ completely inhibited O2 consumption, reduction of ubiquinone-10, and reduction of cytochrome b in a dose-dependent manner. The production of superoxide (O2-) induced by MPP+ or analog 8 was to the same extent as that by rotenone, an inhibitor of complex I of the mitochondrial respiratory chain. Rotenone had no additive effect on the maximal production of O2- induced by MPP+ or analog 8, suggesting that the production was mediated by the same way as rotenone. 1-Methyl-4-(4'-nitrophenyl) pyridinium (analog 1) induced about 20-fold more production of O2 than MPP+ and the production was additively increased by rotenone. Analog 1 only partially inhibited rotenone-sensitive O2 consumption. Paraquat induced the production of O2- as much as analog 1. Paraquat, however, did not inhibit rotenone-sensitive O2 consumption or reduction of cytochrome b. These results suggest that MPP+ and its analogs interact with the mitochondrial respiratory chain at two sites, the substrate side of the rotenone-binding site and the rotenone-binding site. The analogs may be reduced to produce O2- at the former site and inhibit the respiratory chain at the latter site.
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PMID:A dual effect of 1-methyl-4-phenylpyridinium (MPP+)-analogs on the respiratory chain of bovine heart mitochondria. 939 4


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