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)

A novel mitochondrial DNA point mutation, a C-to-A mutation at nucleotide position (np) 11,777, was identified in two unrelated patients out of 100 with Leigh syndrome. This mutation converted a highly evolutionary conserved arginine to a serine at codon 340 in ND4 gene. This codon was also converted by a G-to-A mutation at np 11,778, the most common mutation associated with Leber's hereditary optic neuropathy (LHON), but the amino acid replacement was different (R340S vs. R340H). Cybrid study revealed that the percentage of heteroplasmy was correlated with complex I function and that the novel mutation caused a much more deleterious effect than the np 11,778 LHON mutation in complex I activity.
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PMID:A novel mtDNA C11777A mutation in Leigh syndrome. 1612 Mar 29

Leber's hereditary optic neuropathy (LHON) is associated with mitochondrial DNA point mutations affecting different subunits of complex I. By replacing glucose with galactose in the medium, cybrids harboring each of the three LHON pathogenic mutations (11778/ND4, 3460/ND1, 14484/ND6) suffered a profound ATP depletion over a few hours and underwent apoptotic cell death, which was caspase-independent. Control cybrids were unaffected. In addition to cytochrome c, apoptosis inducing factor (AIF) and endonuclease G (EndoG) were also released from the mitochondria into the cytosol in LHON cybrids, but not in control cells. Exposure of isolated nuclei to cytosolic fractions from LHON cybrids maintained in galactose medium caused nuclear fragmentation, which was strongly reduced by immuno-depletion with anti-AIF and anti-EndoG antibodies. In conclusion, the caspase-independent death of LHON cybrids incubated in galactose medium is triggered by rapid ATP depletion and mediated by AIF and EndoG.
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PMID:Caspase-independent death of Leber's hereditary optic neuropathy cybrids is driven by energetic failure and mediated by AIF and Endonuclease G. 1615 35

Oxygen is a major regulator of nuclear gene expression. However, although mitochondria consume almost all of the O2 available to the cells, little is known about how O2 tension influences the expression of the mitochondrial genome. We show in O2-sensitive excitable rat PC12 cells that, among the mtDNA-encoded genes, hypoxia produced a specific down-regulation of the transcripts encoding mitochondrial complex I NADH dehydrogenase (ND) subunits, particularly ND4 and ND5 mRNAs and a stable mRNA precursor containing the ND5 and cytochrome b genes. This unprecedented effect of hypoxia was fast (developed in <30 min) and fairly reversible and occurred at moderate levels of hypoxia (O2 tensions in the range of 20-70 mm Hg). Hypoxic down-regulation of the mitochondrial complex I genes was paralleled by the reduction of complex I activity and was retarded by iron chelation, suggesting that an iron-dependent post-transcriptional mechanism could regulate mitochondrial mRNA stability. It is known that cell respiration is under tight control by the amount of proteins in mitochondrial complexes of the electron transport chain. Therefore, regulation of the expression of the mitochondrial (mtDNA)-encoded complex I subunits could be part of an adaptive mechanism to adjust respiration rate to the availability of O2 and to induce fast adaptive changes in hypoxic cells.
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PMID:Oxygen tension regulates mitochondrial DNA-encoded complex I gene expression. 1625 62

Heteroplasmic nucleotide polymorphisms are rarely observed in wild animal mitochondrial DNA. The occurrence of such site heteroplasmy is expected to be extremely rare at nonsynonymous sites where the number of nucleotide substitutions per site is low due to functional constraints. This report deals with nonsynonymous mitochondrial heteroplasmy from two wild fish species, chum salmon and Japanese flounder. We detected an A/C nonsynonymous heteroplasmic site corresponding to putative amino acids, Ile or Met, in NADH dehydrogenase subunit-5 (ND5) region of chum salmon. The heteroplasmic site was at the 3rd position of 58th codon. As for Japanese flounder we detected a C/T nonsynonymous heteroplasmic site corresponding to putative amino acids, Leu or Pro, in ND4 region. The heteroplasmic site was at the 2nd position of 450th codon. We also verified heteroplasmy at these sites by sequencing cloned fragments.
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PMID:Nonsynonymous site heteroplasmy in fish mitochondrial DNA. 1628 23

To decipher the pathway of apoptosis induction downstream to caspase-8 activation by exogenous expression of Hippi, an interactor of huntingtin-interacting protein Hip1, we studied apoptosis in HeLa and Neuro2A cells expressing GFP-tagged Hippi. Nuclear fragmentation, caspase-1, caspase-8, caspase-9/caspase-6 and caspase-3 activation were increased significantly in Hippi expressing cells. Cleavage of Bid, release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria were also increased in GFP-Hippi expressing cells. It was observed that caspase-1 and caspase-8 activation was earlier than caspase-3 activation and nuclear fragmentation. Expression of caspase-1, caspase-3 and caspase-7 was increased while anti-apoptotic gene Bcl-2 and mitochondrial genes ND1 and ND4 were reduced in Hippi expressing cells. Besides, the expression SDHA and SDHB, nuclear genes, subunits of mitochondrial complex II were decreased in GFP-Hippi expressing cells. Taken together, we concluded that Hippi expression induced apoptosis by releasing AIF and cytochrome c from mitochondria, activation of caspase-1 and caspase-3, and altering the expression of apoptotic genes and genes involved in mitochondrial complex I and II.
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PMID:Induction of apoptosis in cells expressing exogenous Hippi, a molecular partner of huntingtin-interacting protein Hip1. 1636 50

Mitochondrial transformation of Chlamydomonas reinhardtii has been optimized by using a particle-gun device and cloned mitochondrial DNA or PCR fragments. A respiratory-deficient strain lacking a 1.2-kb mitochondrial DNA region including the left telomere and part of the cob gene could be rescued as well as a double-frameshift mutant in the mitochondrial cox1 and nd1 genes. High transformation efficiency has been achieved (100-250 transformants per microgram of DNA), the best results being obtained with linearized plasmid DNA. Molecular analysis of the transformants suggests that the right telomere sequence can be copied to reconstruct the left telomere by recombination. In addition, both nondeleterious and deleterious mutations could be introduced. Myxothiazol-resistant transformants have been created by introducing a nucleotide substitution into the cob gene. Similarly, an in-frame deletion of 23 codons has been created in the nd4 mitochondrial gene of both the deleted and frameshift recipient strains. These 23 codons are believed to encode the first transmembrane segment of the ND4 protein. This Deltand4 mutation causes a misassembly of complex I, with the accumulation of a subcomplex that is 250-kDa smaller than the wild-type complex I. The availability of efficient mitochondrial transformation in Chlamydomonas provides an invaluable tool for the study of mitochondrial biogenesis and, more specifically, for site-directed mutagenesis of mitochondrially encoded subunits of complex I, of special interest because the yeast Saccharomyces cerevisiae, whose mitochondrial genome can be manipulated virtually at will, is lacking complex I.
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PMID:High-efficiency biolistic transformation of Chlamydomonas mitochondria can be used to insert mutations in complex I genes. 1653 19

The impaired mitochondrial function hypothesis in schizophrenia is based on evidence of altered brain metabolism, morphology, biochemistry and gene expression. Mitochondria have their own genome, which is needed to synthesize some of the subunits of the respiratory chain enzymes. Mitochondrial DNA (mtDNA) is maternally inherited and we observed an excess of maternal transmission of schizophrenia in a set of parent-offspring affected pairs. We therefore hypothesized that mutations in the mtDNA may contribute to the complex genetic basis of schizophrenia. The entire mtDNA of six schizophrenic patients with an apparent maternal transmission of the disease was sequenced and compared to the reference sequence. We have identified 50 variants and among these six have not been previously reported. Three of them were missense variants: MTCO2 7750C>A, MTATP6 8857G>A and MTND4 12096T>A. These were maternally inherited because they were also present in the mtDNA of their respective schizophrenic mothers and none of them were found in 95 control individuals. The MTND4 12096T>A (Leu446His) is a heteroplasmic variant present in five of the six mother-offspring patient pairs that triggers a non-conservative substitution in the ND4 subunit of complex I. Sequence alignment of 110 ND4 peptides from all eukaryotic kingdoms shows that only hydrophobic amino acids are found in this position. Moreover, leucine was conserved or substituted by an isoleucine in all mammalian species. This indicates that the presence of histidine could affect complex I activity in patients with schizophrenia.
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PMID:New variants in the mitochondrial genomes of schizophrenic patients. 1726 66

Onchocerciasis is a serious disease vectored by black flies in the genus Simulium that are infected with the filarial parasite Onchocerca volvulus. In the Americas, black flies of the Simulium ochraceum s.l. species complex are important vectors of this parasite. Cytological studies have suggested that this species complex consists of at least three cytotypes that inhabit distinct habitats. In this study, the NADH dehydrogenase subunit four (ND4) and internal transcribed spacer (ITS) of the ribosomal RNA gene cluster were used to explore the degree of genetic diversity among S. ochraceum s.l. populations found in the three O. volvulus foci in Mexico. Both sequence regions were found to exhibit intra- and interpopulation variation. Four different ND4 alleles were found among the populations examined. Similarly, variation was noted in the ITS domain sequences within and among populations. Variation within the ITS sequence was primarily confined to a complex microsatellite locus. Four ITS length variants were observed, two of which were only seen in flies collected from the onchocerciasis focus in northern Chiapas. These data suggest that the ND4 and ITS sequences may prove to be useful markers for exploring interactions within and among the S. ochraceum s.l. populations in Mexico.
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PMID:Analysis of genetic variation in ribosomal DNA internal transcribed spacer and the NADH dehydrogenase subunit 4 mitochondrial genes of the onchocerciasis vector Simulium ochraceum. 1689 27

The mechanisms responsible for low mitochondrial respiratory chain (MRC) activity in the liver of patients with nonalcoholic steatohepatitis are unknown. In this study, we examined the cause of this dysfunction in ob/ob mice. Forty-six mice were distributed in six groups: group I: C57BL/6J mice; group II: C57BL/6J Lep(-/-) mice (ob/ob); group III, ob/ob mice treated with manganese [III] tetrakis (5,10,15,20 benzoic acid) porphyrin (MnTBAP); group IV, ob/ob mice treated with IgG1 immunoglobulin; group V, ob/ob mice treated with anti-TNF antibody; group VI: ob/ob mice treated with uric acid. In liver tissue, we measured MRC activity, fatty acid beta-oxidation, tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS), 3-tyrosine-nitrated proteins, 3-tyrosine-nitrated mitochondrial proteins, including cytochrome c and ND4 subunit of complex I. MRC activity was decreased in ob/ob mice. TNF levels, iNOS protein expression, and tyrosine nitrated proteins were markedly increased in the liver of ob/ob mice. In these animals, mitochondrial proteins were markedly tyrosine nitrated, particularly the ND4 subunit of complex I and cytochrome c. Treatment of these animals with uric acid, a peroxynitrite scavenger, anti-TNF antibody, or MnTBAP decreased tyrosine nitrated proteins, improved the activity of MRC complexes, and led to a marked regression of hepatic steatosis and inflammation. In conclusion, MRC dysfunction and liver lesions found in ob/ob mice are likely to reflect the tyrosine nitration of mitochondrial proteins by peroxynitrite or a peroxynitrite-derivate radical. Increased hepatic TNF and iNOS expression might enhance peroxynitrite formation and inhibition of MRC complexes.
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PMID:Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice. 1694 82

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


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