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)

Mitochondrial dysfunctions of the muscle in diabetic amyotrophy and of the liver in diabetic fatty liver have been reported. We investigated mitochondrial gene mutations in three cases: (1) a patient with diabetic amyotrophy in the muscles of the lower extremities, and neuropathy; (2) 5 diabetics with myoatrophy, diabetic nephropathy, and chronic renal failure; and (3) an IDDM patient with a diabetic fatty liver. We identified a 5778-bp deletion (8214-13991) in mitochondrial DNA from the muscle and liver biopsy specimens by the primer shift PCR and PCR-direct sequence methods. It is speculated that 5778-bp deletion is due to homogeneous recombination in the 7-bp repeat sequence of TCCTAGA flanking the region deleted in the mitochondrial DNA. Determination of respiratory chain enzyme activities in fresh muscle mitochondria demonstrated the defect in complex I activity. The deletion covers areas coding ND3, ND4, ND4L, and ND5 in complex I. The 5778-bp deletion might cause a defect in mitochondrial oxidative phosphorylation and contribute to the pathogenesis of diabetic amyotrophy, myoatrophy with diabetic nephropathy, and chronic renal failure, as well as diabetic fatty liver in IDDM.
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PMID:A new mitochondrial DNA deletion associated with diabetic amyotrophy, diabetic myoatrophy and diabetic fatty liver. 760 16

The mitochondrial NADH dehydrogenase (complex I) in mammalian cells is a multimeric enzyme consisting of approximately 40 subunits, 7 of which are encoded in mitochondrial DNA (mtDNA). Very little is known about the function of these mtDNA-encoded subunits. In this paper, we describe the efficient isolation from a human cell line of mutants affected in any of these subunits. In the course of analysis of eight mutants of the human cell line VA2B selected for their resistance to high concentrations of the complex I inhibitor rotenone, seven were found to be respiration deficient, and among these, six exhibited a specific defect of complex I. Transfer of mitochondria from these six mutants into human mtDNA-less cells revealed, surprisingly, in all cases a cotransfer of the complex I defect but not of the rotenone resistance. This result indicated that the rotenone resistance resulted from a nuclear mutation, while the respiration defect was produced by an mtDNA mutation. A detailed molecular analysis of the six complex I-deficient mutants revealed that two of them exhibited a frameshift mutation in the ND4 gene, in homoplasmic or in heteroplasmic form, resulting in the complete or partial loss, respectively, of the ND4 subunit; two other mutants exhibited a frameshift mutation in the ND5 gene, in near-homoplasmic or heteroplasmic form, resulting in the ND5 subunit being undetectable or strongly decreased, respectively. It was previously reported (G. Hofhaus and G. Attardi, EMBO J. 12:3043-3048, 1993) that the mutant completely lacking the ND4 subunit exhibited a total loss of NADH:Q1 oxidoreductase activity and a lack of assembly of the mtDNA-encoded subunits of complex I. By contrast, in the mutant characterized in this study in which the ND5 subunit was not detectable and which was nearly totally deficient in complex I activity, the capacity to assemble the mtDNA-encoded subunits of the enzyme was preserved, although with a decreased efficiency or a reduced stability of the assembled complex. The two remaining complex I-deficient mutants exhibited a normal rate of synthesis and assembly of the mtDNA-encoded subunits of the enzyme, and the mtDNA mutation(s) responsible for their NADH dehydrogenase defect remains to be identified. The selection scheme used in this work has proven to be very valuable for the isolation of mutants from the VA2B cell line which are affected in different mtDNA-encoded subunits of complex I and may be applicable to other cell lines.
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PMID:Efficient selection and characterization of mutants of a human cell line which are defective in mitochondrial DNA-encoded subunits of respiratory NADH dehydrogenase. 782 60

The mitochondrial complex I genes were sequenced in seven Leber hereditary optic neuroretinopathy (LHON) families without the ND4/11,778 and ND1/3460 mutations. Four replacement mutations restricted only to LHON families were found, one in the ND1 gene at nt 4025, and three in the ND5 gene at nt 12,811, 13,637, and 13,967. The mutations did not change evolutionarily conserved amino acids suggesting that they are not primary LHON mutations in these families. They may be considered as secondary LHON mutations serving as exacerbating factors in an appropriate genetic background. A complex III mutation, cyt b/15,257, has been suggested to be one of the primary mutations causing LHON. Its presence was determined for 23 Finnish LHON families, and it was detected in two families harboring the ND4/11,778 mutation. Similarly, complex IV mutation COI/7444 was screened in Finnish LHON families, and it was found in one family carrying the ND1/3460 mutation.
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PMID:The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy. 790 Nov 41

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease associated with point mutations in mitochondrial DNA. The most frequent of these mutations is the G-to-A substitution at nucleotide position 11,778 which changes an evolutionarily conserved arginine with a histidine at position 340 in subunit ND4 of NADH:ubiquinone reductase (respiratory complex I). We report that this amino acid substitution alters the affinity of complex I for the ubiquinone substrate and induces resistance towards its potent inhibitor rotenone in mitochondria of LHON patients. Such changes could reflect a substantial loss in the energy conserving function of NADH:ubiquinone reductase and thus explain the pathological effect of the ND4/11,778 mutation.
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PMID:Functional alterations of the mitochondrially encoded ND4 subunit associated with Leber's hereditary optic neuropathy. 792 4

Analyses of the Trypanosoma equiperdum (ATCC 30019) maxicircle reveals deletions, duplications and rearrangement compared to T. brucei. The genes for 9S rRNA and 12 proteins are absent. The 12S rRNA and cytochrome oxidase subunit I (COI) genes lack their 3' ends and are adjacent indicating deletion of intervening genes. The remaining two NADH dehydrogenase subunit genes (ND4 and ND5), the ribosomal protein RPS12 gene and the CR5 gene are duplicated and rearranged. ND4, RPS12 and the CR4 transcripts are abundant in steady state RNA while 12S rRNA and COI transcripts are not detected. Full length ND5 transcripts are rare, if present, but chimeric ND5/ND4 transcripts are abundant. The CR4 and RPS12 transcripts are the size of unedited RNAs suggesting that they are processed. However, they are not edited normally, presumably due to the absence of minicircle gRNA genes.
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PMID:Mitochondrial transcripts are processed but are not edited normally in Trypanosoma equiperdum (ATCC 30019) which has kDNA sequence deletion and duplication. 820 73

The mitochondrion is the only extranuclear organelle containing DNA (mtDNA). As such, genetically determined mitochondrial diseases may result from a molecular defect involving the mitochondrial or the nuclear genome. The first is characterized by maternal inheritance and the second by Mendelian inheritance. Ragged-red fibers (RRF) are commonly seen with primary lesions of mtDNA, but this association is not invariant. Conversely, RRF are seldom associated with primary lesions of nuclear DNA. Large-scale rearrangements (deletions and insertions) and point mutations of mtDNA are commonly associated with RRF and lactic acidosis, e.g. Kearns-Sayre syndrome (KSS) (major large-scale rearrangements), Pearson syndrome (large-scale rearrangements), myoclonus epilepsy with RRF (MERRF) (point mutation affecting tRNA(lys) gene), mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) (two point mutations affecting tRNA(leu)(UUR) gene) and a maternally-inherited myopathy with cardiac involvement (MIMyCa) (point mutation affecting tRNA(leu)(UUR) gene). However, RRF and lactic acidosis are absent in Leber hereditary optic neuropathy (LHON) (one point mutation affecting ND4 gene, two point mutations affecting ND1 gene, and one point mutation affecting the apocytochrome b subunit of complex III), and the condition associated with maternally inherited sensory neuropathy (N), ataxia (A), retinitis pigmentosa (RP), developmental delay, dementia, seizures, and limb weakness (NARP) (point mutation affecting ATPase subunit 6 gene). The point mutations in MELAS, MIMyCa, and MERRF, and the large-scale mtDNA rearrangements in KSS and Pearson syndrome have a broader biochemical impact since these molecular defects involve the translational sequence of mitochondrial protein synthesis. The nuclear defects involving mitochondrial function generally are not associated with RRF. The biochemical classification of mitochondrial diseases principally catalogues these nuclear defects. This classification divides mitochondrial diseases into five categories. Primary and secondary deficiencies of carnitine are examples of a substrate transport defect. A lipid storage myopathy is often present. Disturbances of pyruvate or fatty acid metabolism are examples of substrate utilization defects. Only four defects of the Krebs cycle are known: fumarase deficiency, dihydrolipoyl dehydrogenase deficiency, alpha-ketoglutarate dehydrogenase deficiency, and combined defects of muscle succinate dehydrogenase and aconitase. Luft disease is the singular example of a defect in oxidation-phosphorylation coupling. Defects of respiratory chain function are manifold. Two clinical syndromes predominate, one involving limb weakness, and the other primarily affecting brain function. Leigh syndrome may result from different enzyme defects, most notably pyruvate dehydrogenase complex deficiency, cytochrome c oxidase deficiency, complex I deficiency, and complex V deficiency associated with the recently described NARP point mutation. A new group of mitochondrial diseases has emerged.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The expanding clinical spectrum of mitochondrial diseases. 833 7

In most eukaryotic cells, the respiratory chain NADH dehydrogenase (Complex I) is a multimeric enzyme under dual (nuclear and mitochondrial) genetic control. Several genes encoding subunits of this enzyme have been identified in the mitochondrial genome from various organisms, but the functions of these subunits are in most part unknown. We describe here a human cell line in which the enzyme lacks the mtDNA-encoded subunit ND4 due to a frameshift mutation in the gene. In this cell line, the other mtDNA-encoded subunits fail to assemble, while at least some of the nuclear-encoded subunits involved in the redox reactions appear to be assembled normally. In fact, while there is a complete loss of NADH:Q1 oxidoreductase activity, the NADH:Fe(CN)6 oxidoreductase activity is normal. These observations provide the first clear evidence that the ND4 gene product is essential for Complex I activity and give some insights into the function and the structural relationship of this polypeptide to the rest of the enzyme. They are also significant for understanding the pathogenetic mechanism of the ND4 gene mutation associated with Leber's hereditary optic neuropathy.
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PMID:Lack of assembly of mitochondrial DNA-encoded subunits of respiratory NADH dehydrogenase and loss of enzyme activity in a human cell mutant lacking the mitochondrial ND4 gene product. 834 46

We previously reported the sequencing of two genes (ndhA and ndhI) encoding two of the subunits of the type-I NADH-ubiquinone oxidoreductase from Rhodobacter capsulatus (Rc). The present paper deals with the cloning and characterization of a chromosomal fragment clustering five new Rc genes which encode subunits of this enzyme. This gene cluster is located immediately downstream from ndhA and ndhI, and also contains two unidentified open reading frames (urf2, urf3). The five genes, nuoJ, nuoK, nuoL, nuoM and nuoN, encode proteins related, respectively, to mitochondrial (mt) subunits ND6, ND4L, ND5, ND4 and ND2. The overall organization of the nuo genes identified in Rc shows similarity to that of the Paracoccus denitrificans (Pd) nqo gene cluster.
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PMID:Identification of five Rhodobacter capsulatus genes encoding the equivalent of ND subunits of the mitochondrial NADH-ubiquinone oxidoreductase. 856 20

A rare form of Leber hereditary optic neuropathy (LHON) that is associated with hereditary spastic dystonia has been studied in a large Dutch family. Neuropathy and ophthalmological lesions were present together in some family members, whereas only one type of abnormality was found in others. mtDNA mutations previously reported in LHON were not present. Sequence analysis of the protein-coding mitochondrial genes revealed two previously unreported mtDNA mutations. A heteroplasmic A-->G transition at nucleotide position 11696 in the ND4 gene resulted in the substitution of an isoleucine for valine at amino acid position 312. A second mutation, a homoplasmic T-->A transition at nucleotide position 14596 in the ND6 gene, resulted in the substitution of a methionine for the isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy revealed a severe complex I deficiency, providing a link between these unique mtDNA mutations and this rare, complex phenotype including Leber optic neuropathy.
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PMID:Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia. 864 32

Mitochondrial DNA from two genetically unrelated patients carrying the mutation at position 11778 that causes Leber's hereditary optic neuropathy has been transferred with mitochondria into human mtDNA-less rho0206 cells. As analyzed in several transmitochondrial cell lines thus obtained, the mutation, which is in the gene encoding subunit ND4 of the respiratory chain NADH dehydrogenase (ND), did not affect the synthesis, size, or stability of ND4, nor its incorporation into the enzyme complex. However, NADH dehydrogenase-dependent respiration, as measured in digitonin-permeabilized cells, was specifically decreased by approximately 40% in cells carrying the mutation. This decrease, which was significant at the 99.99% confidence level, was correlated with a significantly reduced ability of the mutant cells to grow in a medium containing galactose instead of glucose, indicating a clear impairment in their oxidative phosphorylation capacity. On the contrary, no decrease in rotenone-sensitive NADH dehydrogenase activity, using a water-soluble ubiquinone analogue as electron acceptor, was detected in disrupted mitochondrial membranes. This is the first cellular model exhibiting in a foreign nuclear background mitochondrial DNA-linked biochemical defects underlying the optic neuropathy phenotype.
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PMID:Respiration and growth defects in transmitochondrial cell lines carrying the 11778 mutation associated with Leber's hereditary optic neuropathy. 866 57


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