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)

Oncocytic tumors are characterized by cells with an aberrant accumulation of mitochondria. To assess mitochondrial function in neoplastic oncocytic cells, we studied the thyroid oncocytic cell line XTC.UC1 and compared it with other thyroid non-oncocytic cell lines. Only XTC.UC1 cells were unable to survive in galactose, a condition forcing cells to rely solely on mitochondria for energy production. The rate of respiration and mitochondrial ATP synthesis driven by complex I substrates was severely reduced in XTC.UC1 cells. Furthermore, the enzymatic activity of complexes I and III was dramatically decreased in these cells compared with controls, in conjunction with a strongly enhanced production of reactive oxygen species. Osteosarcoma-derived transmitochondrial cell hybrids (cybrids) carrying XTC.UC1 mitochondrial DNA (mtDNA) were generated to discriminate whether the energetic failure depended on mitochondrial or nuclear DNA mutations. In galactose medium, XTC.UC1 cybrid clones showed reduced viability and ATP content, similarly to the parental XTC.UC1, clearly pointing to the existence of mtDNA alterations. Sequencing of XTC.UC1 mtDNA identified a frameshift mutation in ND1 and a nonconservative substitution in cytochrome b, two mutations with a clear pathogenic potential. In conclusion, this is the first demonstration that mitochondrial dysfunction of XTC.UC1 is due to a combined complex I/III defect associated with mtDNA mutations, as proven by the transfer of the defective energetic phenotype with the mitochondrial genome into the cybrids.
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PMID:Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III. 1677 81

The electron transport chain enzyme complex I may play a role in Parkinson's disease (PD) pathogenesis. Association studies considering whether or not complex I-relevant gene polymorphisms contribute to PD risk are discordant. We evaluated four complex I-relevant gene polymorphisms alternatively reported to associate and not associate with PD (tRNA(Gln) T4336C, ND1 T4216C, ND2 G5460A, and the NDUFV2 exon 2 C182T transition). Our study included 111 PD subjects and 106 controls in central Virginia. Individuals with at least one copy of the NDUFV2 182T allele were more likely to report a PD family history than non-carriers, but aside from this no positive associations were found. Indeed, the tRNA(Gln) 4336C variant occurred more frequently in controls. We also observed that individuals in both groups often carried more than one of the assayed polymorphisms, and for the first time show bigenomic polymorphic variation (between nuclear and mtDNA complex I subunit genes) commonly occurs within individuals. In an exploratory sub-analysis, more control than case women had an ND1 4216C, NDUFV2 homozygous 182C compound genotype. Complex I compound genotype variation commonly occurs and may explain why particular complex I gene polymorphisms associate with PD in some populations but not others.
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PMID:Complex I polymorphisms, bigenomic heterogeneity, and family history in Virginians with Parkinson's disease. 1678 56

The ND1 subunit gene of the mitochondrial NADH-ubiquinone oxidoreductase (complex I) is a hot spot for mutations causing Leber hereditary optic neuropathy and several mutations causing the mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). We have used Escherichia coli and Paracoccus denitrificans as model systems to study the effect of mutations 3946 and 3949, which change conserved residues in ND1 and cause MELAS. The vicinity of these mutations was also explored with a series of mutations in charged residues. The 3946 mutation results in E214K substitution in human ND1. Replacement of the equivalent residue in E. coli with lysine or glutamine detracted from enzyme assembly and the assembled enzyme was inactive. However, the equivalent E234Q mutant enzyme in P. denitrificans failed to assemble completely (or was rapidly degraded). Also the corresponding substitution with aspartate decreased the enzyme activity in P. denitrificans and E. coli. The 3949-equivalent substitution, Y229H in E. coli, lowered the catalytic activity by 30%. In addition, an activation of the enzyme during catalytic turnover was seen in this bacterial NDH-1, something that was even more pronounced in another mutant in the same loop, D213E. Several other mutations in this region decreased the enzyme activity. The studied MELAS mutations are situated in a matrix-side loop, which appears to be highly sensitive to structural perturbations. The results provide new information on the function of the region affected by the MELAS mutations 3946 and 3949 that is not obtainable from patient samples or current eukaryote models.
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PMID:The MELAS mutations 3946 and 3949 perturb the critical structure in a conserved loop of the ND1 subunit of mitochondrial complex I. 1684 71

We investigated the effect of a change in food consistency on properties of the masseter muscle in 3-week-old rats fed a soft diet for 9 weeks (Group S) and fed a soft diet for 5 weeks followed by a hard diet for 4 weeks (Group S-H). The NADH-O2 oxidoreductase activity, levels of mRNAs transcribed from genes encoding NADH-ubiquinone oxidoreductase (Complex I: ND1, 51kDa, and 75kDa) and myosin heavy chain (MyHC) isoforms and the phenotype of the muscle fibers were measured in the superficial and deep portions of the muscle. In the period from 8 weeks to 12 weeks of age, NADH-O2 oxidoreductase enzyme activity in both the superficial and deep portions of the muscle showed similar patterns in Group S and Group S-H. In contrast, the ND1, 51kDa and 75kDa mRNA levels in the superficial and deep portions of the masseter muscle in the Group S-H were higher than those of Group S in the 12-week-old rats, except for the 51kDa mRNA in the superficial portion of the masseter muscle. MyHC-IIa and MyHC-IId/x mRNA levels in the superficial portion of the masseter muscle were higher in the Group S-H than in the Group S. These observations suggest that short-term feeding stress such as the transition from a soft diet to a hard diet causes changes in oxidative metabolism, in mRNA levels for the Complex I components ND1 and 75kDa, and the mRNA levels for the MyHC isoforms IIa and IId/x in the superficial portion of rat masseter muscle, but no changes in the composition of muscle fiber types.
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PMID:Effect of changes in food consistency on NADH-ubiquinone oxidoreductase activity and levels of mRNA for ND1, 51kDa, 75kDa and myosin heavy chain isoforms in two different portions of rat masseter muscle. 1694 39

Made of more than 40 subunits, the rotenone-sensitive NADH:ubiquinone oxidoreductase (complex I) is the most intricate membrane-bound enzyme of the mitochondrial respiratory chain. In vascular plants, fungi, and animals, at least seven complex I subunits (ND1, -2, -3, -4, -4L, -5, and -6; ND is NADH dehydrogenase) are coded by mitochondrial genes. The role of these highly hydrophobic subunits in the enzyme activity and assembly is still poorly understood. In the unicellular green alga Chlamydomonas reinhardtii, the ND3 and ND4L subunits are encoded in the nuclear genome, and we show here that the corresponding genes, called NUO3 and NUO11, respectively, display features that facilitate their expression and allow the proper import of the corresponding proteins into mitochondria. In particular, both polypeptides show lower hydrophobicity compared to their mitochondrion-encoded counterparts. The expression of the NUO3 and NUO11 genes has been suppressed by RNA interference. We demonstrate that the absence of ND3 or ND4L polypeptides prevents the assembly of the 950-kDa whole complex I and suppresses the enzyme activity. The putative role of hydrophobic ND subunits is discussed in relation to the structure of the complex I enzyme. A model for the assembly pathway of the Chlamydomonas enzyme is proposed.
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PMID:ND3 and ND4L subunits of mitochondrial complex I, both nucleus encoded in Chlamydomonas reinhardtii, are required for activity and assembly of the enzyme. 1696 30

Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder characterized by bilateral loss of central vision, most frequently found in young adult males. In most patients there are no other neurological manifestations and cerebral neuroimaging is normal, but some rare cases of "LHON plus" have been described. Classical LHON is mainly associated to mitochondrial DNA (mtDNA) mutations 11778G>A, 3460G>A and 14484T>C, localized in the coding regions for ND4, ND1 and ND6 of the complex I subunits of mitochondrial respiratory chain (MRC), respectively. We report a 12-year-old girl who presented with reduced visual acuity secondary to optic atrophy at 8 months of age, which led to a clinical diagnosis of LHON. Psychomotor regression, refractory epilepsy and progressive neurological abnormalities developed subsequently. Skeletal muscle histology and biochemical MRC function were normal (evaluated by dual wavelength spectrophotometry). A 11778G>A mtDNA point mutation (investigated by standard PCR and automatic sequencing methods) was identified in lymphocytes isolated from peripheral blood, muscle biopsy and cultured skin fibroblasts. The mother and other maternal relatives are carriers for the same mutation. This case is unusual for age of onset, gender, associated neurological findings and evolution.
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PMID:Atypical presentation of Leber's hereditary optic neuropathy associated to mtDNA 11778G>A point mutation--A case report. 1725 17

The inhibitor binding domain in bovine complex I is believed to be constructed by multisubunits, but it remains to be learned how the binding positions of chemically diverse inhibitors relate to each other. To get insight into the inhibitor binding domain in complex I, we synthesized a photoreactive acetogenin [[125I](trifluoromethyl)phenyldiazirinylacetogenin, [125I]TDA], in which an aryldiazirine group serves as both a photoreactive group and a substitute for the gamma-lactone ring that is a common toxophore of numerous natural acetogenins, and carried out photoaffinity labeling to identify the labeled subunit using bovine heart submitochondrial particles (SMP). When SMP were UV-irradiated in the presence of [125I]TDA, radioactivity was predominantly incorporated into an approximately 30 kDa band on a SDS gel. Blue native gel electrophoresis of the [125I]TDA-labeled SMP revealed that the majority of radioactivity was observed in complex I. Analysis of complex I on a SDS gel showed a predominant peak of radioactivity at approximately 30 kDa. Immnoprecipitation of the [125I]TDA-labeled complex I with anti-bovine ND1 antibody indicated that the labeled protein is the ND1 subunit. A variety of complex I inhibitors such as piericidin A and rotenone efficiently suppressed the specific binding of [125I]TDA to ND1, indicating that they share a common binding domain. However, the suppression efficiency of Deltalac-acetogenin, a new type of complex I inhibitor synthesized in our laboratory, was much lower than that of the traditional inhibitors. Our results unequivocally reveal that the ND1 subunit constructs the inhibitor binding domain, though the contribution of this subunit has been challenged. Further, the present study corroborates our previous proposition that the inhibition site of Deltalac-acetogenins differs from that of traditional inhibitors.
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PMID:The ND1 subunit constructs the inhibitor binding domain in bovine heart mitochondrial complex I. 1747 59

LHON (Leber hereditary optic neuropathy) is a maternally inherited disease that leads to sudden loss of central vision at a young age. There are three common primary LHON mutations, occurring at positions 3460, 11778 and 14484 in the human mtDNA (mitochondrial DNA), leading to amino acid substitutions in mitochondrial complex I subunits ND1, ND4 and ND6 respectively. We have now examined the effects of ND6 mutations on the function of complex I using the homologous NuoJ subunit of Escherichia coli NDH-1 (NADH:quinone oxidoreductase) as a model system. The assembly level of the NDH-1 mutants was assessed using electron transfer from deamino-NADH to the 'shortcut' electron acceptor HAR (hexammine ruthenium), whereas ubiquinone reductase activity was determined using DB (decylubiquinone) as a substrate. Mutant growth in minimal medium with malate as the main carbon source was used for initial screening of the efficiency of energy conservation by NDH-1. The results indicated that NuoJ-M64V, the equivalent of the common LHON mutation in ND6, had a mild effect on E. coli NDH-1 activity, while nearby mutations, particularly NuoJ-Y59F, NuoJ-V65G and NuoJ-M72V, severely impaired the DB reduction rate and cell growth on malate. NuoJ-Met64 and NuoJ-Met72 position mutants lowered the affinity of NDH-1 for DB and explicit C-type inhibitors, whereas NuoJ-Y59C displayed substrate inhibition by oxidized DB. The results are compatible with the notion that the ND6 subunit delineates the binding cavity of ubiquinone substrate, but does not directly take part in the catalytic reaction. How these changes in the enzyme's catalytic properties contribute to LHON pathogenesis is discussed.
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PMID:Leber hereditary optic neuropathy mutations in the ND6 subunit of mitochondrial complex I affect ubiquinone reduction kinetics in a bacterial model of the enzyme. 1789 48

Cells conditioned by repeated treatments with low doses of H(2)O(2,) were compared with its parental V79 cells for expression of ND1 and ND4 subunits of NADH dehydrogenase, a mitochondrial gene. It was found that ND1 and ND4 subunits were overexpressed in these conditioned cells. These cells were also found to be resistant to killing upon gamma-irradiation through suppression of apoptotic cell death. On irradiation, the expression of both subunits decreased in both cell types, but overall there was more expression of both subunits in the conditioned cells. These findings indicate alteration in the expression of NADH dehydrogenase, a mitochondrial gene, could be involved in the recovery of gamma-irradiated cells through inhibition of apoptosis.
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PMID:NADH dehydrogenase subunits are overexpressed in cells exposed repeatedly to H2O2. 1790 12

The mitochondrial NADH:ubiquinone oxidoreductase complex (Complex I) is a large protein complex formed from both nuclearly and mitochondrially encoded subunits. Subunit ND1 is encoded by a mitochondrial gene comprising five exons, and the mature transcript requires four RNA splicing events, two of which involve trans-splicing independently transcribed RNAs. We have identified a nuclear gene (OTP43) absolutely required for trans-splicing of intron 1 (and only intron 1) of Arabidopsis thaliana nad1 transcripts. This gene encodes a previously uncharacterized pentatricopeptide repeat protein. Mutant Arabidopsis plants with a disrupted OTP43 gene do not present detectable mitochondrial Complex I activity and show severe defects in seed development, germination, and to a lesser extent in plant growth. The alternative respiratory pathway involving alternative oxidase is significantly induced in the mutant.
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PMID:The pentatricopeptide repeat gene OTP43 is required for trans-splicing of the mitochondrial nad1 Intron 1 in Arabidopsis thaliana. 1796 68


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