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)

Continuous exposure of Chinese hamster ovary (CHO) cells to an atmosphere of 98% O2, 2% CO2 (normobaric hyperoxia) leads within a period of several days to cytostasis and clonogenic cell death. Here we report respiratory failure as an important early symptom of oxygen intoxication in CHO cells, resulting in a more than 80% inhibition of oxygen consumption within 3 days of hyperoxic exposure. This inhibition appeared to be correlated with selective inactivation of three mitochondrial key enzymes, NADH dehydrogenase, succinate dehydrogenase, and alpha-ketoglutarate dehydrogenase. The latter enzyme controls the influx of glutamate into the Krebs cycle and is particularly critical for oxidative ATP generation in most cultured cells, which depends on exogenous glutamine rather than glucose as a carbon source. As expected, the inactivation of alpha-ketoglutarate dehydrogenase was correlated with a fall in cellular glutamine utilization, which became apparent from the first day of hyperoxic exposure. Thereafter, glucose utilization and lactate excretion started to increase, up to 3-fold, indicating a cellular response to respiratory failure aimed at increased ATP generation from glycolysis. However, in spite of this response, the cellular ATP level progressively decreased, up to 2.5-fold. Thus, killing of CHO cells by normobaric hyperoxia seems to be due to a severe disturbance of mitochondrial metabolism eventually leading to a depletion of cellular ATP pools.
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PMID:Respiratory failure and stimulation of glycolysis in Chinese hamster ovary cells exposed to normobaric hyperoxia. 235 58

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

Partially purified subunits of anthranilate synthase were prepared from Bacillus subtilis and Pseudomonas aeruginosa. The large component from B. subtilis (I(B)) complements well with the small component from P. aeruginosa (II(P)) to reconstitute a glutamine-reactive anthranilate synthase. This interaction can be demonstrated with crude extracts from a B. subtilis trpX mutant and a P. aeruginosa trpA mutant. Complementation was also observed with the large component from P. aeruginosa (I(P)) and the small subunit from B. subtilis (II(B)). At saturation the heterologous complex I(B)II(P) has 93% of the activity of the homologous complex I(B)II(B), whereas the hybrid I(P)II(B) is only 22% as active as the homologous complex I(P)II(P).
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PMID:Intergeneric complementation of anthranilate synthase subunits. 419 46

The nucleotide sequence of the regions flanking the A+T region of Drosophila melanogaster mitochondrial DNA (mtDNA) has been determined. Included are the genes encoding the transfer RNAs for valine, isoleucine, glutamine and methionine, the small ribosomal RNA and the 5'-coding sequences of the large ribosomal RNA and NADH dehydrogenase subunit II. This completes the nucleotide sequence of the D. melanogaster mitochondrial genome. The circular mtDNA of D. melanogaster varies in size among different populations largely due to length differences in the control region (Fauron & Wolstenholme, 1976; Fauron & Wolstenholme, 1980a, b); the mtDNA region we have sequenced, combined with those sequenced by others, yields a composite genome that is 19,517 bp in length as compared to 16,019 bp for the mtDNA of D. yakuba. D. melanogaster mtDNA exhibits an extreme bias in base composition; it comprises 82.2% deoxyadenylate and thymidylate residues as compared to 78.6% in D. yakuba mtDNA. All genes encoded in the mtDNA of both species are in identical locations and orientations. Nucleotide substitution analysis reveals that tRNA and rRNA genes evolve at less than half the rate of protein coding genes.
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PMID:Drosophila melanogaster mitochondrial DNA: completion of the nucleotide sequence and evolutionary comparisons. 882 64

Previous studies have estimated levels of mitochondrial DNA (mtDNA) carrying the 4,977-base-pair 'common deletion' in tissues from patients with Parkinson's disease (PD) by using semiquantitative techniques. The role of this deleted mtDNA species in the pathogenesis of PD has remained controversial. We have applied competitive polymerase chain reaction to achieve exact quantitation of deleted mtDNA in the substantia nigra and additional brain regions of cases with neuropathologically confirmed Lewy-body parkinsonism. In addition, genotyping was carried out for CYP2D6G1,934A and CYP2D6C2,938T alleles and the mitochondrial ND2 (nucleotide 5,460) and transfer RNA for glutamine (nucleotide 4,336) sequence variants. Parkinsonian brains showed 1-3% deleted mtDNA in the substantia nigra, that is, deletion levels were not higher than in age-matched controls. Our findings suggest that the defect in complex I of the respiratory chain observed in PD is not primarily due to the 'common deletion.'
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PMID:The 'common deletion' is not increased in parkinsonian substantia nigra as shown by competitive polymerase chain reaction. 938 43

The NADH-linked substrates pyruvate, L-glutamine, and beta-hydroxybutyrate, while enhancing the rate of oxygen consumption, also increased the formation of DNA single-strand breaks induced by tert-butylhydroperoxide in intact U937 cells. A cause-effect relationship between these two parameters was established by showing that: (a) rotenone, an inhibitor of complex I, abolished respiration and prevented the enhancement of the DNA-damaging response under all the above circumstances; (b) the membrane-impermeant, complex I-activating substrate L-malate gave similar results in permeabilized cells; and (c) none of the NADH-linked substrates affected the DNA-damaging response to tert-butylhydroperoxide in respiration-deficient cells. Stimulation of electron transport potentiated the DNA-cleaving ability of tert-butylhydroperoxide via a process involving enforced mitochondrial calcium accumulation in the absence of a discernible elevation in the cytosolic concentration of free Ca2+. Finally, mitochondrial calcium was found to promote the mitochondrial formation of DNA-damaging levels of hydrogen peroxide. In conclusion, the data herein presented define a previously unexpected role of respiratory substrates in the control of the deleterious effects of an organic hydroperoxide at the level of genomic DNA. The enhanced DNA cleavage mediated by NADH-linked substrates in response to tert-butylhydroperoxide would appear to depend on a sequence of events involving stimulation of electron transport, mitochondrial accumulation of Ca2+, and mitochondrial formation of DNA-damaging levels of hydrogen peroxide via a Ca(2+)-dependent process.
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PMID:Stimulation of oxygen consumption promotes mitochondrial calcium accumulation, a process associated with, and causally linked to, enhanced formation of tert-butylhydroperoxide-induced DNA single-strand breaks. 941 80

The oxidative metabolism of glutamine in HeLa cells was investigated using intact cells and isolated mitochondria. The concentrations of the cytoplasmic amino acids were found to be aspartate, 8.0 mM; glutamate, 22.2 mM; glutamine, 11.3 mM; glycine, 9.8 mM; taurine, 2.3 mM; and alanine, < 1 mM. Incubation of the cells with [14C]glutamine gave steady-state recoveries of 14C-label (estimated as exogenous glutamine) in the glutamine, glutamate, and aspartate pools, of 103%, 80%, and 25%, respectively, indicating that glutamine synthetase activity was absent and that a significant proportion of glutamate oxidation proceeded through aspartate aminotransferase. No label was detected in the alanine pool, suggesting that alanine aminotransferase activity was low in these cells. The clearance rate of [14C]glutamine through the cellular compartment was 65 nmol/min per mg protein. There was a 28 s delay after [14C]glutamine was added to the cell before 14C-label was incorporated into the cytoplasm, while the formation of glutamate commenced 10 s later. Aspartate was the major metabolite formed when the mitochondria were incubated in a medium containing either glutamine, glutamate, or glutamate plus malate. The transaminase inhibitor AOA inhibited both aspartate efflux from the mitochondria and respiration. The addition of 2-oxoglutarate failed to relieve glutamate plus malate respiration, indicating that 2-oxoglutarate is part of a well-coupled truncated cycle, of which aspartate aminotransferase has been shown to be a component [Parlo and Coleman (1984): J Biol Chem 259:9997-10003]. This was confirmed by the observation that, although it inhibited respiration, AOA did not affect the efflux of citrate from the mitochondria. Thus citrate does not appear to be a cycle component and is directly transported to the medium. Therefore, it was concluded that the truncated TCA cycle in HeLa cells is the result of both a low rate of citrate synthesis and an active citrate transporter. DNP (10 microM) induced a state III-like respiration only in the presence of succinate, which supports the evidence that NAD-linked dehydrogenases were not coupled to respiration, and suggests that these mitochondria may have a defect in complex I of the electron transport chain. Arising from the present results with HeLa cells and results extant in the literature, it has been proposed that a major regulating mechanism for the flux of glutamate carbon in tumour cells is the competitive inhibition exerted by 2-oxoglutarate on aspartate and alanine aminotransferases. This has been discussed and applied to the data.
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PMID:Oxidation of glutamine in HeLa cells: role and control of truncated TCA cycles in tumour mitochondria. 944 77

The complete nucleotide sequence of the Chlamydomonas eugametos (Chlamydomonadales, Chlorophyceae, sensu Mattox and Stewart) mitochondrial genome has been determined (22,897 bp, 34.6% G + C). The genes identified in this circular-mapping genome include those for apocytochrome b, subunit 1 of the cytochrome oxidase complex, subunits 1, 2, 4, 5, and 6 of the NADH dehydrogenase complex, discontinuous large and small subunit ribosomal rRNAs and three tRNAs whose anticodons CAU, CCA and UUG are specific for methionine, tryptophan and glutamine, respectively. The C. eugametos mitochondrial DNA (mtDNA), therefore, shares almost the same reduced set of coding functions and similar unusual features of rRNA gene organization with the linear 15.8 kb mtDNA of Chlamydomonas reinhardtii, the only other completely sequenced chlamydomonadalean mtDNA. However, sequence analysis of the C. eugametos mtDNA has revealed the following distinguishing features relative to those of C. reinhardtii: (1) the absence of a reverse transcriptase-like gene homologue, (2) the presence of an additional gene for tRNA(met) that may be a pseudogene, (3) a completely different gene order, (4) transcription of all genes from the same mtDNA strand, (5) a lower G + C content, (6) less pronounced bias in codon usage, and (7) nine group I introns, several of which contain open reading frames coding for potential maturases/endonucleases and two have a nucleotide at the 5' or 3' splice site of the deduced precursor RNAs that deviates from highly conserved nucleotides reported in other group I introns. The features of mitochondrial genome organization and gene content shared by C. eugametos and C. reinhardtii contrast with those of other green algal mtDNAs that have been characterized in detail. The deep evolutionary divergence between these two Chlamydomonas taxa within the Chlamydomonadales suggests that their shared features of mitochondrial genome organization evolved prior to the origin of this group.
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PMID:Complete sequence of the mitochondrial DNA of Chlamydomonas eugametos. 948 40

Proton-translocating NADH:ubiquinone oxidoreductase (complex I) is the largest and least understood enzyme of the respiratory chain. Complex I from bovine mitochondria consists of more than forty different polypeptides. Subunit PSST has been suggested to carry iron-sulfur center N-2 and has more recently been shown to be involved in inhibitor binding. Due to its pH-dependent midpoint potential, N-2 has been proposed to play a central role both in ubiquinone reduction and proton pumping. To obtain more insight into the functional role of PSST, we have analyzed site-directed mutants of conserved acidic residues in the PSST homologous subunit of the obligate aerobic yeast Yarrowia lipolytica. Mutations D136N and E140Q provided functional evidence that conserved acidic residues in PSST play a central role in the proton translocating mechanism of complex I and also in the interaction with the substrate ubiquinone. When Glu(89), the residue that has been suggested to be the fourth ligand of iron-sulfur center N-2 was changed to glutamine, alanine, or cysteine, the EPR spectrum revealed an unchanged amount of this redox center but was shifted and broadened in the g(z) region. This indicates that Glu(89) is not a ligand of N-2. The results are discussedin the light of structural similarities to the homologous [NiFe] hydrogenases.
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PMID:Function of conserved acidic residues in the PSST homologue of complex I (NADH:ubiquinone oxidoreductase) from Yarrowia lipolytica. 1081 5

Tumor necrosis factor (TNF) induces a caspase-independent but mitochondria-dependent cell death process in the mouse fibrosarcoma cell line L929. Mitochondria actively participate in this TNF-induced necrotic cell death by the generation of mitochondrial reactive oxygen species (ROS). The aim of this study was to identify the mitochondrial components involved in TNF-induced production of ROS and their regulation by bioenergetic pathways. Therefore, we analyzed the bioenergetic characteristics in two metabolic L929 variants that exhibit different sensitivities to TNF. L929gln cells use glutamine as respiratory substrate and are far more susceptible to TNF-induced ROS generation and cell death as L929glc cells that use glucose as respiratory substrate. We show that the higher levels of reducing NAD(P)H equivalents, detected in the desensitized L929glc cells, do not cause diminished ROS generation. To the contrary, TNF increases the levels of NAD(P)H, probably altering complex I activity. A multiparameter analysis of electron flux through the mitochondrial electron transport chain, TNF-induced ROS levels, and cell death convincingly demonstrates a dependence of TNF signaling on complex I activity. Also, the sensitizing effect of glutamine metabolism correlates with an enhanced contribution of complex I to the overall electron flux. This participation of complex I activity in TNF-induced cell death is regulated by substrate availability rather than by a direct modification of complex I proteins. From the results presented in this paper we conclude that TNF-induced ROS generation and cell death are strongly regulated by bioenergetic pathways that define electron flux through complex I of the electron transport chain.
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PMID:Regulation of tumor necrosis factor-induced, mitochondria- and reactive oxygen species-dependent cell death by the electron flux through the electron transport chain complex I. 1122 40


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