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)

The nucleotide sequence of a 9240-base pair DNA fragment of the mitochondrial (mt) genome of a squid, Loligo bleekeri, was determined, in which 8 protein and 14 tRNA genes were identified. The gene organization of the mt-genome exhibits a greater resemblance to the gene organization of arthropods and a chiton, Katharina tunicata, than to those of a mussel, Mytilus edulis, and land snails. A cloverleaf-like structure was observed between the genes for subunits 4 and 5 of NADH dehydrogenase (ND4 and -5), which is considered to have originated from histidine tRNA. It is presumed that this structure functions as a transcriptional punctuation signal for the maturation of the ND4 and ND5 mRNAs.
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PMID:Gene contents and organization of a mitochondrial DNA segment of the squid Loligo bleekeri. 1022 73

The activities and mRNA abundances of enzymes that regulate the rate of electron flow through the electron transport chain (ETC), including NADH dehydrogenase, succinate dehydrogenase, and cytochrome c oxidase, were examined in young and senescent fetal lung fibroblasts (WI-38). We also determined the activities and mRNA abundances of antioxidant defenses including superoxide dismutase, catalase, and glutathione peroxidase. We confirmed our previous report of a senescence-related increase in the abundance of ND4, a mitochondrially encoded subunit of NADH dehydrogenase. The activities of cytochrome c oxidase and NADH dehydrogenase were also elevated in senescent cultures. No differences were observed in the mRNA abundances of COX-1, a mitochondrially encoded subunit of cytochrome c oxidase or of nuclearly encoded subunits of various electron transport components (SD, COX-4, and ND 51). Lucigenin-detected chemiluminescence and H2O2 generation were both elevated in senescent cells. Catalase activity was also elevated in senescent fibroblasts. However, no differences in catalase mRNA abundance were observed. A small decrease in GSH peroxidase (GPx) mRNA abundance was observed in senescent cells. No other changes in the activities or mRNA abundances of any of the antioxidant defenses were observed in early and late passage cultures. The relationships between oxidant generation, mitochondrial enzyme activities, and antioxidant defense observed during proliferative senescence are dissimilar to those detected between fetal and postnatal fibroblasts as well as those found between fibroblast lines obtained from young and old individuals. The relevance of the differences between these models is discussed.
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PMID:Differences in electron transport potential, antioxidant defenses, and oxidant generation in young and senescent fetal lung fibroblasts (WI-38). 1036 24

In this study, changes of the expression of two mitochondrial and two nuclear genes encoding the subunits of cytochrome c oxidase (CO) and NADH dehydrogenase (ND) were studied in the hippocampus, inferior parietal lobule, and cerebellum of 10 Alzheimer's disease (AD) and 10 age-matched control subjects. The altered proportion between CO II and CO IV mRNAs was observed in the AD brain. Changes of the proportion between CO II and CO IV transcripts may contribute to the kinetic perturbation of CO documented in AD. A coordinated decrease of ND4 and ND15 mRNAs was found in the AD hippocampus and inferior parietal lobule, but not in cerebellum. The decrease of ND4 gene expression may lead to the inhibition of normal ubiquinone oxidoreductase activity of ND. This study suggests that changes of the expression of mitochondrial and nuclear genes, encoding parts of ND and CO enzyme complexes, may contribute to alterations of oxidative metabolism in AD.
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PMID:The expression of several mitochondrial and nuclear genes encoding the subunits of electron transport chain enzyme complexes, cytochrome c oxidase, and NADH dehydrogenase, in different brain regions in Alzheimer's disease. 1044 60

Kearns-Sayre syndrome is one of the neurological diseases caused by a defect in the energy-producing system of mitochondria. Keams-Sayre is known to be associated with a deletion in the mitochondrial genome and is usually detected in muscle biopsies of the patients. In this study, we report the molecular lesion of mitochondrial DNA (mtDNA) in four Thai patients admitted to hospital with encephalomyopathies. The 3.5-kb deletion of mtDNA was detected by Southern analysis, mapped by amplification with five primer pairs covering almost the total mitochondrial genome, and confirmed by PCR primer shift analysis. The deleted position was localized to nt 10208/13765 or nt 10204/13761 spanning the coding area of subunits 3 (ND3), 4L (ND4L), 4 (ND4), and 5 (ND5) of respiratory chain enzyme complex I and the tRNA genes for histidine, serine, leucine, and arginine. The sequence flanking the deletion was a 4-bp repeat of TCCC. All four patients have exactly the same 3558-bp mtDNA deletion; this is the only deleted position in their mtDNA but is different from those reported in the literature. The deletion seems to be found only in Thai patients, although they present with different clinical manifestations and none of them is not related.
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PMID:A unique 3.5-kb deletion of the mitochondrial genome in Thai patients with Kearns-Sayre syndrome. 1048 Mar 66

Many of the membrane-bound protein complexes of respiratory and photosynthetic systems are reactive with quinones. To date, no clear structural relationship between sites that bind quinone has been defined, apart from that in the homologous family of "type II" photosynthetic reaction centres. We show here that a structural element containing a weak sequence motif is common to the Q(A) and Q(B) sites of bacterial reaction centres and the Q(i) site of the mitochondrial bc(1) complex. Analyses of sequence databases indicate that this element may also be present in the PsaA/B subunits of photosystem I, in the ND4 and ND5 subunits of complex I and, possibly, in the mitochondrial alternative quinol oxidase. This represents a first step in the structural classification of quinone binding sites.
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PMID:A motif for quinone binding sites in respiratory and photosynthetic systems. 1068 11

Complete sequence analysis of all mitochondrial complex I genes was performed in 22 cases of neuropathologically confirmed idiopathic Parkinson disease (PD). DNA from the substantia nigra was used as a template for polymerase chain reaction-based genomic sequencing. Seven novel mutations causing the exchange of amino acids were detected in subunit genes ND1 (3992 C/ T, 4024 A/G), ND4 (11253 T/C, 12084 C/T), ND5 (13711 G/A, 13768 T/C), and ND6 (14582 T/C). In addition, five known missense mutations affecting the ND1 (3335 T/C, 3338 T/C), ND2 (5460 G/A), ND3 (10398 A/G), and ND5 (13966 A/G) genes as well as three secondary LHON mutations (4216 T/C, 4917 A/ G, 13708 G/A) were found in the PD group. Among the novel mutations, the 11253 T/C transition which changes a conserved isoleucine residue into threonine is most likely to be of functional relevance. Furthermore, 43 synonymous polymorphisms were detected in PD brains, including 20 novel sequence variants. Haplogroup analysis revealed that most unique missense mutations were found in PD cases belonging to the D(c) haplogroup. Our data are in line with the view that PD is not a single disease entity but comprises a genetically heterogeneous group of disorders. The results of our study further suggest that 90% or more of all idiopathic PD cases are not due to sequence variation of mitochondrial complex I, but that mitochondrial mutations may play a pathogenic role in a subset of PD patients.
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PMID:Novel mutations of mitochondrial complex I in pathologically proven Parkinson disease. 1073 23

In the present work, a large scale investigation was done regarding the capacity of cultured human cell lines (carrying in homoplasmic form either the mitochondrial tRNA(Lys) A8344G mutation associated with the myoclonic epilepsy and ragged red fiber (MERRF) encephalomyopathy or a frameshift mutation, isolated in vitro, in the gene for the ND4 subunit of NADH dehydrogenase) to undergo transcomplementation of their recessive mitochondrial DNA (mtDNA) mutations after cell fusion. The presence of appropriate nuclear drug resistance markers in the two cell lines allowed measurements of the frequency of cell fusion in glucose-containing medium, non-selective for respiratory capacity, whereas the frequency of transcomplementation of the two mtDNA mutations was determined by growing the same cell fusion mixture in galactose-containing medium, selective for respiratory competence. Transcomplementation of the two mutations was revealed by the re-establishment of normal mitochondrial protein synthesis and respiratory activity and by the relative rates synthesis of two isoforms of the ND3 subunit of NADH dehydrogenase. The results of several experiments showed a cell fusion frequency between 1.4 and 3.4% and an absolute transcomplementation frequency that varied between 1.2 x 10(-5) and 5.5 x 10(-4). Thus, only 0.3-1.6% of the fusion products exhibited transcomplementation of the two mutations. These rare transcomplementing clones were very sluggish in developing, grew very slowly thereafter, and showed a substantial rate of cell death (22-28%). The present results strongly support the conclusion that the capacity of mitochondria to fuse and mix their contents is not a general intrinsic property of these organelles in mammalian cells, although it may become activated in some developmental or physiological situations.
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PMID:Very rare complementation between mitochondria carrying different mitochondrial DNA mutations points to intrinsic genetic autonomy of the organelles in cultured human cells. 1075 28

Complex I (NADH:ubiquinone oxidoreductase) purified from bovine heart mitochondria was treated with the detergent N, N-dimethyldodecylamine N-oxide (LDAO). The enzyme dissociated into two known subcomplexes, Ialpha and Ibeta, containing mostly hydrophilic and hydrophobic subunits, and a previously undetected fragment referred to as Igamma. Subcomplex Igamma contains the hydrophobic subunits ND1, ND2, ND3, and ND4L which are encoded in the mitochondrial genome, and the nuclear-encoded subunit KFYI. During size-exclusion chromatography in the presence of LDAO, subcomplex Ialpha lost several subunits and formed another characterized subcomplex known as Ilambda. Similarly, subcomplex Ibeta dissociated into two smaller subcomplexes, one of which contains the hydrophobic subunits ND4 and ND5; subcomplex Igamma released a fragment containing ND1 and ND2. These results suggest that in the intact complex subunits ND1 and ND2 are likely to be in a different region of the membrane domain than subunits ND4 and ND5. The compositions of the various subcomplexes and fragments of complex I provide an organization of the subunits of the enzyme in the framework of the known low resolution structure of the enzyme.
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PMID:Resolution of the membrane domain of bovine complex I into subcomplexes: implications for the structural organization of the enzyme. 1085 22

NADH:ubiquinone oxidoreductase (complex I) is the first and largest enzyme of the mitochondrial respiratory chain. The low-resolution structure of the complex is known from electron microscopy studies. The general shape of the complex is in the form of an L, with one arm in the membrane and the other peripheral. We have purified complex I from beef heart mitochondria and reconstituted the enzyme into lipid bilayers. Under different conditions, several two-dimensional crystal forms were obtained. Crystals belonging to space groups p222(1) and c12 (unit cell 488 Ax79 A) were obtained at 22 degrees C and contained only the membrane fragment of complex I similar to hydrophobic subcomplex Ibeta but lacking the ND5 subunit. A crystal form with larger unit cell (534 Ax81 A, space group c12) produced at 4 degrees C contained both the peripheral and membrane arms of the enzyme, except that ND5 was missing. Projection maps from frozen hydrated samples were calculated for all crystal forms. By comparing two different c12 crystal forms, extra electron density in the projection map of large crystal form was assigned to the peripheral arm of the enzyme. One of the features of the map is a deep, channel-like, cleft next to peripheral arm. Comparison with available structures of the intact enzyme indicates that large hydrophobic subunit ND5 is situated at the distal end of the membrane domain. Possible locations of subunit ND4 and of other subunits in the membrane domain are proposed. Implications of our findings for the mechanism of proton pumping by complex I are discussed.
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PMID:Cryo-electron crystallography of two sub-complexes of bovine complex I reveals the relationship between the membrane and peripheral arms. 1097 Jul 45

We employed a microphotometric approach to examine whether a defect in the mitochondrial respiratory complex I expected in Leber hereditary optic neuropathy (LHON) as the consequence of a mtDNA (11778G>A) mutation in the ND4 gene coding for a subunit of the respiratory complex I can be detected at the single-cell level. Genetically stable fibroblast cell lines were established from skin biopsies of two members of a Chinese Indonesian family with LHON. The fibroblasts were homoplasmic for the 11778G>A mutation. The activity of the respiratory complex I was examined histochemically by staining for NADH-tetrazolium reductase. The histochemical staining showed a typical pattern with an apparent concentration of the activity around the nucleus, suggested as the reflection of the gradient in the thickness of the unsectioned fibroblast cells. Microphotometric quantification of the staining intensity showed that the activity is linear for at least 60 min. The activity shows a discontinuity in its Arrhenius kinetics with a break point at 13.0-13.5 degrees C (activation energy at 50-58 J/mol and 209-238 J/mol above and below the break temperature, respectively), indicating the membrane association of the NADH-tetrazolium reductase activity. Both patients showed lower fibroblast NADH-tetrazolium reductase activity, with a reduction of degrees 30%. Our results demonstrate the utility of microphotometric analysis in the study of biochemical defects associated with mutations in the mtDNA.
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PMID:Microphotometric analysis of NADH-tetrazolium reductase deficiency in fibroblasts of patients with Leber hereditary optic neuropathy. 1111 34


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