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 electron transfer complexes, succinate: ubiquinone reductase, ubiquinone: cytochrome c reductase, and cytochrome c: O2 oxidase were isolated from the mitochondrial membranes of Neurospora crassa by the following steps. Modification of the contents of the complexes in mitochondria by growing cells on chloramphenicol; solubilisation of the complexes by Triton X-100; affinity chromatography on immobilized cytochrome c and ion exchange and gel chromatography. Ubiquinone reductase was obtained in a monomeric form (Mr approximately 130 000) consisting of a flavin subunit (Mr 72 000) an iron-sulfur subunit (Mr 28 000) and a cytochrome b subunit (Mr probably 14 000). Cytochrome c reductase was obtained in a dimeric form (Mr approximately 550 000), the monomeric unit comprising the cytochromes b (Mr each 30 000), a cytochrome c1 (Mr 31 000), the iron-sulfur subunit (Mr 25 000), and six subunits without known prosthetic groups (Mr 9000, 11 000, 14 000, 45 000, 45 000, and 52 000). Cytochrome c oxidase was also isolated in a dimeric form (Mr approximately 320 000) comprising two copies each of seven subunits (Mr 9000, 12 000, 14 000, 18 000, 21 000, 29 000, and 40 000). The complexes were essentially free of phospholipid. Each bound one micelle of Triton X-100 (Mr approximately 90 000). After isolation, the bound Triton X-100 could be replaced by other nonionic detergents such as: alkylphenyl polyoxyethylene ethers, alkyl polyoxyethylene ethers and acyl polyoxyethylene sorbitan esters.
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PMID:Isolation of mitochondrial succinate: ubiquinone reductase, cytochrome c reductase and cytochrome c oxidase from Neurospora crassa using nonionic detergent. 22 65

The polypeptide encoded in URF6, the last unassigned reading frame of human mitochondrial DNA, has been identified with antibodies to peptides predicted from the DNA sequence. Antibodies prepared against highly purified respiratory chain NADH dehydrogenase from beef heart or against the cytoplasmically synthesized 49-kilodalton iron-sulfur subunit isolated from this enzyme complex, when added to a deoxycholate or a Triton X-100 mitochondrial lysate of HeLa cells, specifically precipitated the URF6 product together with the six other URF products previously identified as subunits of NADH dehydrogenase. These results strongly point to the URF6 product as being another subunit of this enzyme complex. Thus, almost 60% of the protein coding capacity of mammalian mitochondrial DNA is utilized for the assembly of the first enzyme complex of the respiratory chain. The absence of such information in yeast mitochondrial DNA dramatizes the variability in gene content of different mitochondrial genomes.
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PMID:URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit. 376 30

The structural organization of the entire human nuclear encoded gene for the 24-kDa iron-sulfur subunit of mitochondrial NADH-ubiquinone oxidoreductase (Complex I) and its chromosomal localization were determined. The gene contains 8 exons spanning 31.5 kb. The 5' flanking region sequenced lacks typical CAAT and TATA boxes but contains three putative GC boxes and there is one GC box at the beginning of the first intron. The sequences matching completely with the NRF-1 binding site and Mt elements were not identified in the flanking region. This gene was assigned to human chromosome 18 at region p11.3, by fluorescent in situ hybridization.
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PMID:Structural organization and chromosomal localization of the human nuclear gene (NDUFV2) for the 24-kDa iron-sulfur subunit of complex I in mitochondrial respiratory chain. 748 92

We have isolated cDNA clones encoding an iron-sulfur polypeptide subunit of the mitochondrial complex I of Neurospora crassa. The fungal cDNA library was screened by hybridisation with an heterologous probe from Paracoccus denitrificans. The DNA sequence of relevant isolates was determined and revealed an open reading frame encoding a precursor protein of 219 amino acid residues. The gene product is a ferredoxin-like protein that contains two cysteine-rich motives that may each bind a tetranuclear iron-sulfur cluster. The primary structure of the protein is highly homologous to the 23 kDa iron-sulfur subunit of complex I from bovine and P. denitrificans. Interestingly, an alanine residue within the second cluster-binding motif, which is conserved in complex I but replaced by tyrosine in similar chloroplast genes, is substituted for serine in N. crassa.
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PMID:Primary structure of a ferredoxin-like iron-sulfur subunit of complex I from Neurospora crassa. 869 31

The proton-translocating NADH-quinone oxidoreductase (NDH-1) of Paracoccus denitrificans is composed of at least 14 unlike subunits and contains one FMN and at least five EPR-detectable iron-sulfur clusters. The 14 subunits are designated NQO1 through NQO14. The expression and partial characterization of the NQO4, -5, and -6 subunits have been performed. The NQO4, -5, and -6 subunits were individually expressed in Escherichia coli. The NQO4 subunit was expressed in both the cytoplasmic phase and membrane fraction, the NQO5 subunit in the cytoplasmic phase only, and the NQO6 subunit in the membrane fraction only. The NQO4 and NQO5 subunits were purified from cytoplasmic phase. Neither subunit contains non-heme iron or acid-labile sulfide, suggesting that the NQO4 or NQO5 subunit is not an iron-sulfur subunit. The antibodies against the NQO4, -5, and -6 subunits cross-reacted with their counterpart subunits in bovine heart complex I. The NQO4, -5, and -6 subunits in membrane-bound P. denitrificans NDH-1 were extracted by treatment at alkaline pH ( > or = 10) or with chaotropes (NaBr, Nal, and urea), suggesting that these subunits are localized in the peripheral part (not in the membrane sector) of the enzyme complex similar to the NQO1, -2, and -3 subunits. In addition, the subunit stoichiometry of NQO1 through -6 of the membrane-bound P. denitrificans NDH-1 has been determined by radioimmunoassays. There is 1 mol each of the NQO1 through -6 subunits per mol of the P. denitrificans NDH-1.
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PMID:Structural studies of the proton-translocating NADH-quinone oxidoreductase (NDH-1) of Paracoccus denitrificans: identity, property, and stoichiometry of the peripheral subunits. 870 16

The Saccharomyces cerevisiae succinate-ubiquinone reductase or succinate dehydrogenase (SDH) is a tetramer of non-equivalent subunits encoded by the SDH1, SDH2, SDH3, and SDH4 genes. In most organisms, SDH contains one or two endogenous b-type hemes. However, it is widely believed that the yeast SDH does not contain heme. In this report, we demonstrate the presence of a stoichiometric amount of cytochrome b562 in the yeast SDH. The cytochrome is detected as a peak present in fumarate-oxidized, dithionite-reduced mitochondria. The peak is centered at 562 nm and is present at a heme:covalent FAD molar ratio of 0.92+/-0.11. The cytochrome is not detectable in mitochondria isolated from SDH3 and SDH4 deletion strains. These observations strongly support our conclusion that cytochrome b562 is a component of the yeast SDH.
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PMID:The Saccharomyces cerevisiae succinate-ubiquinone reductase contains a stoichiometric amount of cytochrome b562. 992 2

Obesity and type 2 diabetes have been associated with a high-fat diet (HFD) and reduced mitochondrial mass and function. We hypothesized a HFD may affect expression of genes involved in mitochondrial function and biogenesis. To test this hypothesis, we fed 10 insulin-sensitive males an isoenergetic HFD for 3 days with muscle biopsies before and after intervention. Oligonucleotide microarray analysis revealed 297 genes were differentially regulated by the HFD (Bonferonni adjusted P < 0.001). Six genes involved in oxidative phosphorylation (OXPHOS) decreased. Four were members of mitochondrial complex I: NDUFB3, NDUFB5, NDUFS1, and NDUFV1; one was SDHB in complex II and a mitochondrial carrier protein SLC25A12. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC1) alpha and PGC1beta mRNA were decreased by -20%, P < 0.01, and -25%, P < 0.01, respectively. In a separate experiment, we fed C57Bl/6J mice a HFD for 3 weeks and found that the same OXPHOS and PGC1 mRNAs were downregulated by approximately 90%, cytochrome C and PGC1alpha protein by approximately 40%. Combined, these results suggest a mechanism whereby HFD downregulates genes necessary for OXPHOS and mitochondrial biogenesis. These changes mimic those observed in diabetes and insulin resistance and, if sustained, may result in mitochondrial dysfunction in the prediabetic/insulin-resistant state.
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PMID:A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. 1598 91

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

The killer lymphocyte protease granzyme A (GzmA) triggers caspase-independent target cell death with morphological features of apoptosis. We previously showed that GzmA acts directly on mitochondria to generate reactive oxygen species (ROS) and disrupt the transmembrane potential (DeltaPsi(m)) but does not permeabilize the mitochondrial outer membrane. Mitochondrial damage is critical to GzmA-induced cell death since cells treated with superoxide scavengers are resistant to GzmA. Here we find that GzmA accesses the mitochondrial matrix to cleave the complex I protein NDUFS3, an iron-sulfur subunit of the NADH:ubiquinone oxidoreductase complex I, after Lys56 to interfere with NADH oxidation and generate superoxide anions. Target cells expressing a cleavage site mutant of NDUFS3 are resistant to GzmA-mediated cell death but remain sensitive to GzmB.
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PMID:Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death. 1848 62

Mitochondrial respiratory enzymes play a central role in energy production in aerobic organisms. They differentiated from the alpha-proteobacteria-derived ancestors by adding noncatalytic subunits. An exception is Complex II (succinate: ubiquinone reductase), which is composed of four alpha-proteobacteria-derived catalytic subunits (SDH1-SDH4). Complex II often plays a pivotal role in adaptation of parasites in host organisms and would be a potential target for new drugs. We purified Complex II from the parasitic protist Trypanosoma cruzi and obtained the unexpected result that it consists of six hydrophilic (SDH1, SDH2N, SDH2C, and SDH5-SDH7) and six hydrophobic (SDH3, SDH4, and SDH8-SDH11) nucleus-encoded subunits. Orthologous genes for each subunit were identified in Trypanosoma brucei and Leishmania major. Notably, the iron-sulfur subunit was heterodimeric; SDH2N and SDH2C contain the plant-type ferredoxin domain in the N-terminal half and the bacterial ferredoxin domain in the C-terminal half, respectively. Catalytic subunits (SDH1, SDH2N plus SDH2C, SDH3, and SDH4) contain all key residues for binding of dicarboxylates and quinones, but the enzyme showed the lower affinity for both substrates and inhibitors than mammalian enzymes. In addition, the enzyme binds protoheme IX, but SDH3 lacks a ligand histidine. These unusual features are unique in the Trypanosomatida and make their Complex II a target for new chemotherapeutic agents.
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PMID:Novel mitochondrial complex II isolated from Trypanosoma cruzi is composed of 12 peptides including a heterodimeric Ip subunit. 1912 94


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