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)

We report on the variant phenotypic expression of mitochondrial genotypes in cultured skin fibroblasts and Epstein-Barr virus-transformed lymphocyte cultures from a patient with Pearson syndrome (McKusick no. 260560). Both cell types harbored a heteroplasmic population of normal and deleted mtDNA molecules. The deletion encompassed five tRNA genes and seven genes encoding subunits of cytochrome c oxidase, complex I, and ATPase. Patient skin fibroblasts and lymphocytes harbored 60 and 80% of deleted mtDNA molecules, respectively, and initially displayed defective respiratory chain activities. In both cases, there was a progressive recovery of respiratory chain activities during in vitro cell proliferation. In cultured skin fibroblasts, the loss of the deleted mtDNA molecules accounted for the recovery of normal respiratory chain activities. These features were prevented by allowing respiratory chain-deficient cells to grow in the presence of uridine (200 microM). In Epstein-Barr virus-transformed lymphocytes containing 60% of deleted mtDNA, the recovery of respiratory chain activities was attributable to an increase in the mtRNA translation efficiency rather than to an increased content in mtDNA or mtRNA. The present study suggests that the variant cellular responses to abnormal mitochondrial genotypes might contribute to the tissue-specific expression of mitochondrial disorders in vivo.
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PMID:Fate and expression of the deleted mitochondrial DNA differ between human heteroplasmic skin fibroblast and Epstein-Barr virus-transformed lymphocyte cultures. 839 36

A heteroplasmic G-to-A transition at nucleotide pair (np) 14459 within the mitochondrial DNA (mtDNA)-encoded NADH dehydrogenase subunit 6 (ND6) gene has been identified as the cause of Leber hereditary optic neuropathy (LHON) and/or pediatric-onset dystonia in three unrelated families. This ND6 np 14459 mutation changes a moderately conserved alanine to a valine at amino acid position 72 of the ND6 protein. Enzymologic analysis of mitochondrial NADH dehydrogenase (complex I) with submitochondrial particles isolated from Epstein-Barr virus-transformed lymphoblasts revealed a 60% reduction (P < 0.005) of complex I-specific activity in patient cell lines compared with controls, with no differences in enzymatic activity for complexes II plus III, III and IV. This biochemical defect was assigned to the ND6 np 14459 mutation by using transmitochondrial cybrids in which patient Epstein-Barr virus-transformed lymphoblast cell lines were enucleated and the cytoplasts were fused to a mtDNA-deficient (p 0) lymphoblastoid recipient cell line. Cybrids harboring the np 14459 mutation exhibited a 39% reduction (p < 0.02) in complex I-specific activity relative to wild-type cybrid lines but normal activity for the other complexes. Kinetic analysis of the np 14459 mutant complex I revealed that the Vmax of the enzyme was reduced while the Km remained the same as that of wild type. Furthermore, specific activity was inhibited by increasing concentrations of the reduced coenzyme Q analog decylubiquinol. These observations suggest that the np 14459 mutation may alter the coenzyme Q-binding site of complex I.
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PMID:Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia. 862 78

Human cultured cells are widely used for the investigation of respiratory chain disorders. Oxidative properties are generally investigated by means of polarographic studies carried out on detergent-permeabilized cells. By studying the oxidative properties of Epstein- Barr virus-transformed B lymphocytes, we found that the respiration was significantly decreased after 3-4 days of cell culture. Simultaneously, we observed decreased NAD(+)-dependent oxidations (malate, glutamate, pyruvate) that became dependent upon the addition of exogenous NAD+. The effect of NAD+ was shown to be related to an influx of catalytic amount of NAD+ into the mitochondrial matrix. A full ability to oxidize NAD(+)-dependent substrates was restored less than 2 h after a change of the culture medium. These observations suggested: (a) the occurrence of fluxes of catalytic amounts of NAD+ through the mitochondrial inner membrane in human cells; (b) an early control of mitochondrial metabolism by matrix NAD+ content in cells grown under limiting growth conditions; (c) the possible confusion between complex I deficiency and a decrease content of matrix NAD+ when using human cultured cells.
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PMID:Nicotinamide adenine dinucleotides permeate through mitochondrial membranes in human Epstein-Barr virus-transformed lymphocytes. 930 74

To accomplish the remarkable task of lifelong infection, the Epstein-Barr virus (EBV) switches between four viral genome latency and lytic programmes to navigate the B-cell compartment and evade immune responses. The transforming programme, consisting of highly immunogenic EBV nuclear antigen (EBNA) and latent membrane proteins (LMPs), is expressed in newly infected B lymphocytes and in post-transplant lymphomas. On memory cell differentiation and in most EBV-associated Burkitt's lymphomas, all but one viral antigen are repressed for immunoevasion. To gain insights into the epigenetic mechanisms that restrict immunogenic oncoprotein expression, a genome-scale CRISPR-Cas9 screen was performed in EBV and Burkitt's lymphoma cells. Here, we show that the ubiquitin ligase ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) and its DNA methyltransferase partner DNA methyltransferase I (DNMT1) are critical for the restriction of EBNA and LMP expression. All UHRF1 reader and writer domains were necessary for silencing and DNMT3B was identified as an upstream viral genome CpG methylation initiator. Polycomb repressive complex I exerted a further layer of control over LMP expression, suggesting a second mechanism for latency programme switching. UHRF1, DNMT1 and DNMT3B are upregulated in germinal centre B cells, the Burkitt's lymphoma cell of origin, providing a molecular link between B-cell state and the EBV latency programme. These results suggest rational therapeutic targets to manipulate EBV oncoprotein expression.
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PMID:DNA methylation enzymes and PRC1 restrict B-cell Epstein-Barr virus oncoprotein expression. 3242 39