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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Na+,K(+)-ATPase (the sodium pump) is a ubiquitous enzyme that consumes ATP to maintain an adequate neuronal transmembrane electrical potential necessary for brain function and to dissipate ionic transients. Reductions in sodium pump function augment the sensitivity of neurons to glutamate, increasing excitability and neuronal damage in vitro. Temporal lobe epilepsy (TLE) is one disease characterized by hyperexcitability and marked hippocampal neuronal losses that could depend in part, on impaired sodium pump capacity secondary to changes in sodium pump levels and/or insufficient ATP supply. To assess whether abnormalities in the sodium pump occur in this disease, we used [3H]ouabain to determine the density of Na+,K(+)-ATPase for each anatomic region of hippocampus by in vitro autoradiography. Tissues were surgically obtained from epileptic patients with hippocampal sclerosis and compared with specimens from patients with seizures originating from temporal lobe tumors and autopsy controls. Changes in cellular population arising from neuronal losses or gliosis were assessed by protein densities derived from quantitative computerized densitometry of Coomassie-stained tissue sections. We estimated regional differences in capacity for ATP generation by determining cytochrome c oxidase (CO) activity. Principal neurons of hippocampus exhibit high levels of sodium pump enzyme. Both epilepsy groups exhibited slight but significant increases in sodium pump density/unit mass of protein in the dentate molecular layer, CA2, and subiculum as compared with autopsy controls. Greater hilar sodium pump density was also observed in sclerotic hippocampi. In contrast, CO activity was reduced in both epilepsy types throughout hippocampus. Results suggest that although sodium pump protein in surviving neurons appears to be upregulated in epilepsy, sodium pump capacity may be limited by the reduced levels of CO activity. Functional reduction in sodium pump capacity may be an important factor in hyperexcitability and neuronal death.
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PMID:Regional distributions of hippocampal Na+,K(+)-ATPase, cytochrome oxidase, and total protein in temporal lobe epilepsy. 760 16

Membrane preparations from the green alga Chlamydomonas reinhardtii contain both thylakoid and mitochondrial membranes [1]. These preparations have been intensely used to study the structure, function and biogenesis of protein complexes involved in the photosynthetic pathway. We show here that these preparations are also suitable for studying protein complexes of the mitochondrial respiratory chain of the alga. The respiratory complexes, fractionated on a sucrose gradient in the presence of Triton X-100, were identified by their catalytic properties and their polypeptide content. From the bottom to the top of the sucrose gradient, we identified the NADH: ubiquinone oxidoreductase (complex I), the mitochondrial ATP synthase (F0F1-ATPase), the cytochrome bc1 complex and the cytochrome c oxidase. At the top of the gradient, another enzyme was detected which displayed an NADH: menaquinone oxidoreductase activity.
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PMID:Identification of mitochondrial respiratory proteins from the green alga Chlamydomonas reinhardtii. 782 32

The effects of BRB-I-28 and its derivatives (GLG-V-13, SAZ-VII-22 and SAZ-VII-23), a novel group of antiarrhythmic agents, were investigated on the rat heart mitochondrial respiratory chain. The results indicate that BRB-I-28 and its derivatives have concentration-dependent inhibitory effects on NADH oxidase and NADH-CoQ reductase (complex I), but they have no significant effects on succinate oxidase, succinate dehydrogenase (complex II), CoQ-cytochrome c reductase (complex III), cytochrome c oxidase (complex IV), and NADH-K3Fe(CN)6 reductase. The site of inhibition of BRB-I-28 and its derivatives on the respiratory chain was localized between flavoprotein n (FPn) and CoQ, which is similar to the effect of rotenone and several other antiarrhythmic drugs such as amiodarone, propranolol, etc. BRB-I-28 and its derivatives also have significant inhibitory effects on mitochondrial ATPase activity as reported for other antiarrhythmic drugs such as amiodarone, propranolol, quinidine, and lidocaine. However, BRB-I-28 and its derivatives have no direct effects on sarcoplasmic reticulum Ca(2+)-ATPase activity. The inhibitory effects of BRB-I-28 and its derivatives on mitochondrial oxidative phosphorylation may result in the depletion of ATP. This effect, in combination with their effects on Na+,K(+)-ATPase, could possibly produce an increase in Ca2+ concentration in cytosol. This may be another mechanism by which these DHBCN derivatives produce an increase in systemic arterial blood pressure and contractile force of isolated cardiac muscle. On the other hand, inhibition on mitochondrial respiration may account for some of the potential toxic effects of these diheterabicyclo[3.3.1]nonane derivatives.
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PMID:Effects of novel antiarrhythmic agents, BRB-I-28 and its derivatives, on the heart mitochondrial respiratory chain and sarcoplasmic reticulum Ca(2+)-ATPase. 799 64

The herbicides 2,4-D (2,4-dichlorophenoxyacetic acid) and dinoseb (2-sec-butyl-4,6-dinitrophenol), were tested in mitochondria because they are putative toxins to the organisms. To understand the toxic mechanisms involved, we have determined if mitochondrial bioenergetic functions are affected. Dinoseb partially inhibits uncoupled respiration, reflecting its limited interaction with the mitochondrial redox chain at the level of succinate dehydrogenase and cytochrome c reductase (complex III). Additionally, it increased the rate of state 4 oxygen consumption, stimulated ATPase activity, induced permeabilization of membrane mitochondria to H+, and depressed delta psi. These data characterize dinoseb as a classical proton uncoupler. The herbicide 2,4-D decreased delta psi as a function of concentration and the rate of repolarization was also progressively decreased. State 3 and uncoupled respiration were depressed by approximately the same extent (60%), ruling out interactions on phosphorylation assembly independent of the redox chain. The herbicide strongly inhibited succinate dehydrogenase and cytochrome c reductase (complex III), whereas cytochrome c oxidase was not affected. Additionally, 2,4-D also uncoupled mitochondria at concentrations 1000-fold higher than those required for a similar dinoseb effect. This study therefore suggests that dinoseb- and 2,4-D-induced cellular damage, as we have reported before, is putatively preceded by injury upon bioenergetic functions of mitochondria.
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PMID:Interactions of herbicides 2,4-D and dinoseb with liver mitochondrial bioenergetics. 804 53

We report a unique heteroplasmic T-to-C transition at nucleotide 9997 in the mitochondrial tRNA(glycine) gene in a multiplex family who manifested nonobstructive cardiomyopathy. The degree of mtDNA heteroplasmy generally correlated with the severity of the symptoms. This T-to-C transition disrupts hydrogen bonding in the region adjacent to the acceptor stem of the tRNA molecule. The thymine residue at position 9997 is highly conserved in mammals, as well as in various vertebrates and invertebrates. A PCR diagnostic test for the presence of the 9997 T-to-C transition revealed that the base change was always present in high proportion in affected family members, not present in unaffected family members, and never present in control subjects from various ethnic groups (25 groups sampled, 42 individuals), thus ruling out the possibility that this change represents a polymorphic variant in the general population. The degree of heteroplasmy in lymphoblast cultures also correlated with the level of enzyme activity present for cytochrome c oxidase (complex IV) and succinate cytochrome c oxidoreductase (complexes II and III). The absence of previously reported mtDNA mutations associated with hypertrophic cardiomyopathy was verified by both PCR diagnostic procedures and sequence analysis. All mitochondrial tRNA genes, as well as genes encoding ATPase subunits 6 and 8, were sequenced and found not to possess base changes consistent with the clinical profile. More detailed biochemical and molecular biological investigations are discussed.
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PMID:Maternally inherited hypertrophic cardiomyopathy due to a novel T-to-C transition at nucleotide 9997 in the mitochondrial tRNA(glycine) gene. 807 88

The germinating asexual spores (conidia) of Neurospora crassa were employed to study steps in the accumulation of transcripts of groups of mitochondrial genes, including those for peptide subunits of cytochrome c oxidase (CO), ATPase (ATP), and apocytochrome b (COB). Physically clustered groups of genes were expressed as cohorts: transcripts of the ATP8-ATP6-mtATP9-CO2 genes were almost undetectable in the dormant spores, and they accumulated rapidly as a group immediately after spore activation. Transcripts of COB and the adjacent CO1 were abundant in the dormant spores, and the dormant and germinating spores contained size forms of the COB transcripts that were not evident in vegetative cells. Polyribosomes were prepared from mitochondrial lysates, and the polyribosomal RNA was probed to identify the mRNAs of specific genes; in several instances polycistronic mRNAs were present in the polyribosomes as were the smaller end-products of the inferred transcript processing pathways. The expression of the physically dispersed genes for subunit peptides of cytochrome c oxidase appears to be regulated to the level of translation; these transcripts are accumulated in the total mitochondrial RNA with sharply different kinetics, but they appeared in the polyribosomes uniformly, their appearance correlating with the uniform synthesis of the subunit peptides. Transcripts for a previously reported non-functional mitochondrial gene, homologous to the functional nuclear gene for ATPase subunit 9, were found in the germinating spores, but were not detected in vegetative cells. These mtATP9 transcripts were also present in the polyribosomes and were apparently translated into a protein in vivo whose synthesis was insensitive to cycloheximide and detectable with an anti-ATP9 subunit antibody. Transcripts for two nuclear genes for mitochondrially localized proteins, ATP9 and CO5, were accumulated in unison and especially rapidly during spore germination.
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PMID:Expression of mitochondrial genes in the germinating conidia of Neurospora crassa. 828 26

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

Skeletal muscle specimens from three patients with inclusion body myositis, aged 39, 60 and 71 years, respectively, were investigated. Enzyme histochemical staining of cytochrome c oxidase (COX), succinate dehydrogenase and myofibrillar ATPase, and in situ hybridization of transcripts of mitochondrial DNA (mtDNA) were performed on consecutive sections. In all three cases a proportion of muscle fibres (2-5%) showed low or absent COX activity in spite of medium or high succinate dehydrogenase activity (COX deficient muscle fibres). Two probes detecting transcripts of different segments of mtDNA were used for the in situ hybridization. One of the probes (ND4 probe) detected transcripts of a segment of the NADH dehydrogenase subunit 4 gene, which is known to be affected in most cases of mitochondrial myopathy with large deletions of mtDNA. There was reduced hybridization of the ND4 probe in many COX deficient muscle fibres compared with adjacent normal fibres. The other probe (ND2 probe) detected transcripts of a segment of the NADH dehydrogenase subunit 2 gene, which usually is not included in mtDNA deletions. There was accumulation of transcripts corresponding to the ND2 probe in COX deficient fibres in all three cases. These findings demonstrate that deleted mtDNA had accumulated in COX deficient muscle fibres in patients with inclusion body myositis. Southern blot analysis of mtDNA in muscle revealed a 16.6 kb fragment corresponding to normal mtDNA in all three cases. In one case two additional less abundant fragments of smaller size, corresponding to deleted mtDNA, were detected. Ultrastructural investigation showed abnormal mitochondria in all three cases. Control muscle specimens were obtained from nine patients, aged 63-71 years, with muscle pain but without morphological evidence of muscle disease. Occasional COX deficient fibres (< 1%) were found in three of the control cases. The other six control cases showed no COX deficient fibres. Our results show that mtDNA deletions may be involved in the pathogenesis of inclusion body myositis and cause respiratory chain dysfunction in muscle fibre segments.
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PMID:Mitochondrial DNA deletions in inclusion body myositis. 838 16

It has been suggested that mutations accumulated in mitochondrial DNA during the aging process may be causally related to the decreased physiological response of the senescent organisms. We have quantified and evaluated the integrity of the mitochondrial genome during the life span of Drosophila melanogaster. Its amount remains fairly constant representing roughly 1% of the total DNA at all ages. Southern experiments have also revealed a high stability and integrity of the mitochondrial DNA (mtDNA). However, we have detected an important decrease in the steady-state levels of all mitochondrial transcripts investigated: 16 S ribosomal RNA (16SrRNA), cytochrome c oxidase, cytochrome b, and beta H(+)-ATP synthase subunit. These changes correlate with the shape of the life span curve, preceding the decrease in survival of the male flies used in the study, and at least in the case of 16SrRNA, is tissue-specific. Although mitochondrial DNA remains unchanged in heads, thoraces, and abdomens, 16SrRNA levels decrease more severely in heads and thoraces and much less conspicuously in abdomens. On the other hand, control non-mitochondrial transcripts investigated remain essentially unaffected. These results suggest that in Drosophila the main effect of aging on the mitochondrial genetic system is downstream from mtDNA itself. The decline in the levels of beta H(+)-ATPase transcript, nuclear-encoded, suggests that not only the mitochondrial machinery, but also the nuclear one involved in mitochondrial biogenesis, is affected during aging.
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PMID:Mitochondrial DNA remains intact during Drosophila aging, but the levels of mitochondrial transcripts are significantly reduced. 839 21

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


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