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:3.6.3.14 (ATP synthase)
7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe a four-generation family with a maternally inherited mitochondrial disorder. The symptoms were restricted to the CNS and muscle, the most common features being subacute necrotizing encephalomyopathy, cognitive impairment, ataxia, retinitis pigmentosa, infantile spasms, and optic atrophy. A point mutation at the nucleotide 8993 of the gene encoding subunit 6 of the ATP synthase, associated with the neurogenic muscle weakness, ataxia, retinitis pigmentosa (NARP) syndrome, was shown to be inherited maternally in this family, and a clear correlation was found between the clinical severity of the disease and the proportion of mutant mtDNA. Analysis of oxidative phosphorylation in mitochondria carrying 80% mutant mitochondrial DNA showed a reduction of the ATP generation rate coupled to substrate oxidation.
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PMID:Correlation between the clinical symptoms and the proportion of mitochondrial DNA carrying the 8993 point mutation in the NARP syndrome. 760 83

The mitochondrial ATPase 6 gene encodes a subunit of F1F0 adenosine triphosphate (ATP) synthase. A mutation in the ATPase 6 gene has been genetically linked to two maternally inherited genetic diseases: neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP) and certain cases of subacute necrotizing encephalopathy (SNE). Although the severity of both NARP and SNE disease were correlated with the quantity of the ATPase 6leu156-->arg mutation in each patient, the mutation could not be shown to alter F1F0-ATP synthase activity. To investigate the biochemical effects of the ATPase 6leu156-->arg mutation on F1F0-ATP synthase, the aleu207-->arg mutation was constructed in the F1F0-ATP synthase from Escherichia coli to serve as a model for the disease mutation. Characterization of the model bacterial enzyme revealed that the mutation abolishes detectable ATP synthesis via oxidative phosphorylation. The aleu207-->arg mutation results in a structural perturbation blocking proton translocation through F1F0-ATP synthase. The results suggest that a structural defect in human F1F0-ATP synthase is the biochemical basis for NARP and SNE.
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PMID:The aleu207-->arg mutation in F1F0-ATP synthase from Escherichia coli. A model for human mitochondrial disease. 850 61

To obtain a better molecular definition of patients with syndromic retinitis pigmentosa, we screened for mitochondrial DNA (mtDNA) alterations of the two ATPase genes and 22 tRNA-coding sequences in 10 patients whose features resembled NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome. In two patients, one of whom showed features mimicking Kearns-Sayre syndrome, we identified a heteroplasmic T8993G mutation (average 80%) in the mitochondrial ATPase 6 gene. There was no mutated mtDNA in muscle and leukocytes from the mother of one patient or in leukocytes from his brother, suggesting a rapid segregation of the mutated nucleotide. MtDNA analysis should be considered in the differential diagnosis of patients with syndromic retinitis pigmentosa.
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PMID:Heterogeneous clinical presentation of the mtDNA NARP/T8993G mutation. 922 7

A T --> G mutation at position 8993 in human mitochondrial DNA is associated with the syndrome neuropathy, ataxia, and retinitis pigmentosa and with a maternally inherited form of Leigh's syndrome. The mutation substitutes an arginine for a leucine at amino acid position 156 in ATPase 6, a component of the F0 portion of the mitochondrial ATP synthase complex. Fibroblasts harboring high levels of the T8993G mutation have decreased ATP synthesis activity, but do not display any growth defect under standard culture conditions. Combining the notions that cells with respiratory chain defects grow poorly in medium containing galactose as the major carbon source, and that resistance to oligomycin, a mitochondrial inhibitor, is associated with mutations in the ATPase 6 gene in the same transmembrane domain where the T8993G amino acid substitution is located, we created selective culture conditions using galactose and oligomycin that elicited a pathological phenotype in T8993G cells and that allowed for the rapid selection of wild-type over T8993G mutant cells. We then generated cytoplasmic hybrid clones containing heteroplasmic levels of the T8993G mutation, and showed that selection in galactose-oligomycin caused a significant increase in the fraction of wild-type molecules (from 16 to 28%) in these cells.
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PMID:Oligomycin induces a decrease in the cellular content of a pathogenic mutation in the human mitochondrial ATPase 6 gene. 1009 18

Mutations in human mitochondrial DNA are a well recognized cause of disease. A mutation at nucleotide position 8993 of human mitochondrial DNA, located within the gene for ATP synthase subunit 6, is associated with the neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP) syndrome. To enable analysis of this mutation in control nuclear backgrounds, two different cell lines were transformed with mitochondria carrying NARP mutant mitochondrial DNA. Transformant cell lines had decreased ATP synthesis capacity, and many also had abnormally high levels of two ATP synthase sub-complexes, one of which was F(1)-ATPase. A combination of metabolic labeling and immunoblotting experiments indicated that assembly of ATP synthase was slowed and that the assembled holoenzyme was unstable in cells carrying NARP mutant mitochondrial DNA compared with control cells. These findings indicate that altered assembly and stability of ATP synthase are underlying molecular defects associated with the NARP mutation in subunit 6 of ATP synthase, yet intrinsic enzyme activity is also compromised.
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PMID:Impaired ATP synthase assembly associated with a mutation in the human ATP synthase subunit 6 gene. 1107 46

The oxidative stress resulting from the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the mitochondrial ATPase 6 gene was investigated in cultured skin fibroblasts from two patients presenting an isolated complex V deficiency. Taken as an index for superoxide overproduction, a huge induction of the superoxide dismutase (SOD) activity was observed in these fibroblasts harboring >90% of mutant mitochondrial DNA. The oxidative stress denoted by the high SOD activity was associated with increased cell death. In glucose-rich medium, apoptosis appeared as the main cell death process associated with complex V deficiency. Complex V-deficient fibroblasts, which showed a high SOD induction and stained positive for all studied apoptosis markers, were successfully rescued by perfluoro-tris-phenyl nitrone, an antioxidant spin-trap molecule. This established that the superoxide production associated with the ATPase deficiency triggered by the NARP mutation could be sufficient to override cell antioxidant defenses and to result in cell commitment to die. The potential participation of superoxides and/or their derivatives in the pathogenic mechanism of specific respiratory chain disorders makes them a promising target for therapy.
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PMID:Superoxide-induced massive apoptosis in cultured skin fibroblasts harboring the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the ATPase-6 gene of the mitochondrial DNA. 1137 15

Maternally inherited mutations in the mtDNA-encoded ATPase 6 subunit of complex V (ATP synthase) of the respiratory chain/oxidative phosphorylation system are responsible for a subgroup of severe and often-fatal disorders characterized predominantly by lesions in the brain, particularly in the striatum. These include NARP (neuropathy, ataxia, and retinitis pigmentosa), MILS (maternally inherited Leigh syndrome), and FBSN (familial bilateral striatal necrosis). Of the five known pathogenic mutations causing these disorders, four are located at two codons (156 and 217), each of which can suffer mutations converting a conserved leucine to either an arginine or a proline. Based on the accumulating data on both the structure of ATP synthase and the mechanism by which rotary catalysis couples proton flow to ATP synthesis, we propose a model that may help explain why mutations at codons 156 and 217 are pathogenic.
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PMID:Pathogenesis of primary defects in mitochondrial ATP synthesis. 1173 78

Mutations in the ATP6 gene of mtDNA (mitochondrial DNA) have been shown to cause several different neurological disorders. The product of this gene is ATPase 6, an essential component of the F1F0-ATPase. In the present study we show that the function of the F1F0-ATPase is impaired in lymphocytes from ten individuals harbouring the mtDNA T8993G point mutation associated with NARP (neuropathy, ataxia and retinitis pigmentosa) and Leigh syndrome. We show that the impaired function of both the ATP synthase and the proton transport activity of the enzyme correlates with the amount of the mtDNA that is mutated, ranging from 13-94%. The fluorescent dye RH-123 (Rhodamine-123) was used as a probe to determine whether or not passive proton flux (i.e. from the intermembrane space to the matrix) is affected by the mutation. Under state 3 respiratory conditions, a slight difference in RH-123 fluorescence quenching kinetics was observed between mutant and control mitochondria that suggests a marginally lower F0 proton flux capacity in cells from patients. Moreover, independent of the cellular mutant load the specific inhibitor oligomycin induced a marked enhancement of the RH-123 quenching rate, which is associated with a block in proton conductivity through F0 [Linnett and Beechey (1979) Inhibitors of the ATP synthethase system. Methods Enzymol. 55, 472-518]. Overall, the results rule out the previously proposed proton block as the basis of the pathogenicity of the mtDNA T8993G mutation. Since the ATP synthesis rate was decreased by 70% in NARP patients compared with controls, we suggest that the T8993G mutation affects the coupling between proton translocation through F0 and ATP synthesis on F1. We discuss our findings in view of the current knowledge regarding the rotary mechanism of catalysis of the enzyme.
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PMID:Inefficient coupling between proton transport and ATP synthesis may be the pathogenic mechanism for NARP and Leigh syndrome resulting from the T8993G mutation in mtDNA. 1640 16

Mitochondrial encephalomyopathies are common and devastating multisystem genetic disorders characterized by neuromuscular dysfunction and tissue degeneration. Point mutations in the human mitochondrial ATP6 gene are known to cause several related mitochondrial disorders: NARP (neuropathy, ataxia, and retinitis pigmentosa), MILS (maternally inherited Leigh's syndrome), and FBSN (familial bilateral striatal necrosis). We identified a pathogenic mutation in the Drosophila mitochondrial ATP6 gene that causes progressive, adult-onset neuromuscular dysfunction and myodegeneration. Our results demonstrate ultrastructural defects in the mitochondrial innermembrane, neural dysfunction, and a marked reduction in mitochondrial ATP synthase activity associated with this mutation. This Drosophila mutant recapitulates key features of the human neuromuscular disorders enabling detailed in vivo studies of these enigmatic diseases.
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PMID:Mitochondrial encephalomyopathy in Drosophila. 1642 1

The molecular pathogenic mechanism of the human mitochondrial diseases neurogenic ataxia and retinitis pigmentosa and maternally inherited Leigh syndrome was determined in cultured human cells harboring homoplasmic T8993G/T8993C point mutations in the mitochondrial ATP6 gene, which encodes subunit 6 of the F1F0-ATP synthase. Immunoprecipitation and blue native electrophoresis showed that F1F0-ATP synthase assembles correctly in homoplasmic mutant mitochondria. The mutants exhibited a tendency to have an increased sensitivity to subsaturating amounts of oligomycin; this provided further evidence for complete assembly and tight coupling between the F1 and F0 sectors. Furthermore, human ATP synthase dimers and higher homo-oligomers were observed for the first time, and it was demonstrated that the mutant enzymes retain enough structural integrity to oligomerize. A reproducible increase in the proportion of oligomeric-to-monomeric enzyme was found for the T8993G mutant suggesting that F1F0 oligomerization is regulated in vivo and that it can be modified in pathological conditions. Despite correct assembly, the T8993G mutation produced a 60% inhibition in ATP synthesis turnover. In vitro denaturing conditions showed F1F0 instability conferred by the mutations, although this instability did not produce enzyme disassembly in the conditions used for determination of ATP synthesis. Taken together, the data show that the primary molecular pathogenic mechanism of these deleterious human mitochondrial mutations is functional inhibition in a correctly assembled ATP synthase. Structural instability may play a role in the progression of the disease under potentially denaturing conditions, as discussed.
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PMID:ATP6 homoplasmic mutations inhibit and destabilize the human F1F0-ATP synthase without preventing enzyme assembly and oligomerization. 1712 62


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