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)

Mitochondrial (mt)DNA mutations contribute to various disease states characterized by low ATP production. In contrast, thyroid hormone [3,3',5-triiodothyronine (T(3))] induces mitochondrial biogenesis and enhances ATP generation within cells. To evaluate the role of T(3)-mediated mitochondrial biogenesis in patients with mtDNA mutations, three fibroblast cell lines with mtDNA mutations were evaluated, including two patients with Leigh's syndrome and one with hypertrophic cardiomyopathy. Compared with control cells, patient fibroblasts displayed similar levels of mitochondrial mass, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), mitochondrial transcription factor A (Tfam), and uncoupling protein 2 (UCP2) protein expression. However, patient cells exhibited a 1.6-fold elevation in ROS production, a 1.7-fold elevation in cytoplasmic Ca2+ levels, a 1.2-fold elevation in mitochondrial membrane potential, and 30% less complex V activity compared with control cells. Patient cells also displayed 20-25% reductions in both cytochrome c oxidase (COX) activity and MnSOD protein levels compared with control cells. After T(3) treatment of patient cells, ROS production was decreased by 40%, cytoplasmic Ca2+ was reduced by 20%, COX activity was increased by 1.3-fold, and ATP levels were elevated by 1.6-fold, despite the absence of a change in mitochondrial mass. There were no significant alterations in the protein expression of PGC-1alpha, Tfam, or UCP2 in either T(3)-treated patient or control cells. However, T(3) restored the mitochondrial membrane potential, complex V activity, and levels of MnSOD to normal values in patient cells and elevated MnSOD levels by 21% in control cells. These results suggest that T(3) acts to reduce cellular oxidative stress, which may help attenuate ROS-mediated damage, along with improving mitochondrial function and energy status in cells with mtDNA defects.
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PMID:Effect of thyroid hormone on mitochondrial properties and oxidative stress in cells from patients with mtDNA defects. 1903 42

Mitochondria are central players in the pathophysiology of ischemia-reperfusion. Activation of plasma membrane G-coupled receptors or the Na,K-ATPase triggers cytosolic signaling pathways that result in cardioprotection. Our working hypothesis is that the occupied receptors migrate to caveolae, where signaling enzymes are scaffolded into signalosomes that bud off the plasma membrane and migrate to mitochondria. The signalosome-mitochondria interaction then initiates intramitochondrial signaling by opening the mitochondrial ATP-sensitive K(+) channel (mitoK(ATP)). MitoK(ATP) opening causes an increase in ROS production, which activates mitochondrial protein kinase C epsilon (PKCvarepsilon), which inhibits the mitochondrial permeability transition (MPT), thus decreasing cell death. We review the experimental findings that bear on these hypotheses and other modes of protection involving mitochondria.
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PMID:Cardioprotective signaling to mitochondria. 1911 60

Organisms living at high altitude are exposed to severe environmental stress associated with decreased oxygen pressure, cold temperatures, increased levels of UV radiation, steep slopes, and scarce food supplies, which may have imposed important selective constraints on the evolution of the mitochondrial genome. Within mammals, the tribe Caprini is of particular interest for studying the evolutionary effects of life at high altitude, as most species live in mountain regions, where they developed morphological and physiological adaptations for climbing. In this report, we analyzed the complete mitochondrial genome of 24 ruminants, including 20 species of Caprini. The phylogenetic analyses based on 16,117 nucleotides suggested the existence of a new large clade, here named subtribe Caprina, containing all genera, but Pantholops (Pantholopina), Capricornis, Naemorhedus, and Ovibos (Ovibovina). The alignment of the control region showed that all Caprini have between two and four tandem repeats of ~75 bp in the RS2 region, and that several of these copies emerged from recent and independent duplication events. We proposed therefore that the maintenance of at least two RS2 repeats in the control region of Caprini is positively selected, probably for producing a higher number of D-loop strands 3'-ending at different locations. The analyses of base composition at third-codon positions of protein-coding genes revealed that Caprini have the highest percentage of A nucleotide and the lowest percentage of G nucleotide, a pattern which suggests increased rates of cytosine deamination (C-->T transitions) on the H strand of mtDNA. Two nonexclusive hypotheses related to high-altitude life can explain such a mutational pattern: more severe oxidative stress (ROS) and higher metabolic rates. By comparing the relative rates of nonsynonymous and synonymous substitutions in protein-coding genes, we identified that Caprini have higher levels of adaptive variation in the ATPase complex. In addition, we detected several changes in mitochondrial genes that should be tested for their potential role in mountain adaptation.
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PMID:Evolution of the mitochondrial genome in mammals living at high altitude: new insights from a study of the tribe Caprini (Bovidae, Antilopinae). 1929 54

The Mitchell Theory implies the proton motive force Deltap across the inner mitochondrial membrane as the energy-rich intermediate of oxidative phosphorylation. Deltap is composed mainly of an electrical (DeltaPsi(m)) and a chemical part (DeltapH) and generated by the respiratory chain complexes I, III and IV. It is consumed mostly by the ATP synthase (complex V) to produce ATP. The free energy of electron transport within the proton pumps is sufficient to generate Deltap of about 240 mV. The proton permeability of biological membranes, however, increases exponentially above 130 mV leading to a waste of energy at high values (DeltaPsi(m)>140 mV). In addition, at DeltaPsi(m)>140 mV, the production of the superoxide radical anion O(2)(-) at complexes I, II and III increases exponentially with increasing DeltaPsi(m). O(2)(-) and its neutral product H(2)O(2) (=ROS, reactive oxygen species) induce oxidative stress which participates in aging and in the generation of degenerative diseases. Here we describe a new mechanism which acts independently of the Mitchell Theory and keeps DeltaPsi(m) at low values through feedback inhibition of complex IV (cytochrome c oxidase) at high ATP/ADP ratios, thus preventing the formation of ROS and maintaining high efficiency of oxidative phosphorylation.
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PMID:New extension of the Mitchell Theory for oxidative phosphorylation in mitochondria of living organisms. 1940 64

The influence ofnitric oxide on Na+,K(+)-ATPase activity in rat aorta was studied by means of stimulation of endogenous NO synthesis after injections of bacterial lipopolysaccharide (LPS) and pharmacological NO donor nitroglycerine (NG). It was shown that NO action on Na+,K(+)-ATPase in vivo is dose-dependent. Stimulation of the endogenous NO synthesis by LPS as well as the administration of low doses of NG lead to the activation of Na+,K(+)-ATPase and favor the conclusion that NO-dependent Na+,K(+)-ATPase stimulation mediates vasodilatory and hypotensive action of nitric oxide. The Na+,K(+)-ATPase activity in rat aorta depends on the balance between the level of reactive oxygen and nitrogen species (ROS and RNS), formation of NO depots in the tissue of aorta as high- and low molecular weight nitrosothiols, and also on the intensity of free-radical reactions resulting in the generation of hydroperoxide radicals. The results obtained suggest that NOS- and cGMP-dependent pathway takes part in Na+,(+)-ATPase activation by LPS and NG, but the enzyme inhibition by nitric oxide in vivo is not cGMP-dependent and is determined by the activation of free-radical reactions and dramatic enhancement of nitrosylation level in rat aorta tissue.
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PMID:[Effect of nitric oxide on Na+, K(+)-ATPase in the aorta tissue of rats]. 1944 12

Normal functions of mitochondria are required for physiological dynamics of cells, while their dysfunction contributes to development of various disorders including those of immune system. Here we demonstrate that exposure of mast cells to ragweed pollen extract increases production of H(2)O(2) via mitochondrial respiratory complex III. These mitochondrial ROS (mtROS) enhance secretion of histamine and serotonin from mast cells, but not enzymes such as beta-hexosaminidase, independently from FcvarepsilonRI-generated stimuli. The release of biogenic amines is associated with inhibition of secretory granules' H(+)-ATPase activity, activation of PKC-delta and microtubule-dependent motility, and it is independent from intracellular free Ca(2+) levels. To asses differences from IgE-mediated mast cell degranulation we show that mtROS decrease antigen-triggered beta-hexosaminidase release, while they are synergistic with antigen-induced IL-4 production in sensitized cells. Taken together, these data indicate that mitochondrial dysfunction can act independently from adaptive immunity, as well as augments Th2-type responses. Pharmacological maintenance of physiological mitochondrial function could have clinical benefits in prevention and treatment of allergic diseases.
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PMID:Ragweed pollen-mediated IgE-independent release of biogenic amines from mast cells via induction of mitochondrial dysfunction. 1950 9

Signaling cascades initiated or regulated by calcium (Ca(2+)), reactive oxygen (ROS), and nitrogen (RNS) species are essential to diverse physiological and pathological processes in vascular smooth muscle. Stimuli-induced changes in intracellular Ca(2+) regulate the activity of primary ROS and RNS, producing enzymes including NADPH oxidases (Nox) and nitric oxide synthases (NOS). At the same time, alteration in intracellular ROS and RNS production reciprocates through redox-based post-translational modifications altering Ca(2+) signaling networks. These may include Ca(2+) pumps such as sarcoplasmic endoplasmic reticulum Ca(2+)-ATPase (SERCA), voltage-gated channels, transient receptor potential canonical (TRPC), melastatin2 (TRPM2), and ankyrin1 (TRPA1) channels, store operated Ca(2+) channels such as Orai1/stromal interaction molecule 1 (STIM1), and Ca(2+) effectors such as Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). In this review, we summarize and highlight current experimental evidence supporting the idea that cross-talk between Ca(2+) and ROS/RNS may represent a well-integrated signaling network in vascular smooth muscle.
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PMID:Interplay between calcium and reactive oxygen/nitrogen species: an essential paradigm for vascular smooth muscle signaling. 1971 86

Increased expression of Na(+)/H(+) exchanger (NHE) and Na(+),K(+)-ATPase activity have been demonstrated in diabetic nephropathy and are implicated in the development of hypertension. The aim of this study was to investigate the effect of a synthetic manganese porphyrin SOD mimic and peroxynitrite scavenger, Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin (MnTM-2-PyP) on the expression of NHE and Na(+),K(+)-ATPase activity in the kidneys of streptozotocin (STZ) diabetic rats. MnTM-2-PyP administration (1 mg/kg/day) started immediately after STZ and lasted 2 months. Glucose and glycosylated hemoglobin levels were measured in blood. NHE-1 and NHE-3 isoform expression, Na(+),K(+)-ATPase activity, and markers of ROS/RNS-induced damage were determined in kidney homogenates. Diabetes caused lipid peroxidation, inactivation of aconitase, and increase of nitrotyrosine, which paralleled an increase in NHE-1 and NHE-3 expression and Na(+),K(+)-ATPase activity. MnTM-2-PyP treatment had no effect on blood glucose and glycosylated hemoglobin, but suppressed lipid peroxidation and nitrotyrosine, protected aconitase against inactivation, and reversed the induction of NHE-1 and NHE-3 isoforms. Na(+)/H(+) exchanger is under the control of redox-based cellular transcriptional activity, including members of the SP family of transcription factors. Mn(III) alkylpyridylporphyrins were previously found to inhibit activation of major transcription factors, including SP-1 via scavenging of signaling ROS/RNS. Therefore, our data suggest that, by reducing the levels of ROS/RNS, MnTM-2-PyP might interfere with signaling pathways responsible for NHE up-regulation.
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PMID:Effect of potent redox-modulating manganese porphyrin, MnTM-2-PyP, on the Na(+)/H(+) exchangers NHE-1 and NHE-3 in the diabetic rat. 2000 8

Acute exposure of acetaminophen (APAP), a widely used analgesic and antipyretic drug, causes severe renal damage and no specific agent has been reported so far that plays any beneficial role in this organ pathophysiology. In the present study, the protective role of taurine on APAP-induced nephrotoxicity was investigated in mice. In order to induce acute nephrotoxicity, APAP was administered at a single dose of 2g/kg body weight orally to male adult albino mice of Swiss strain. APAP exposure for 24h significantly increased plasma level of blood urea nitrogen (BUN), creatinine, uric acid, TNF-alpha, NO production, urinary gamma-glutamyl transpeptidase (gamma-GT) activity, total urinary protein and urinary glucose level accompanied by a decrease in Na(+)-K(+)-ATPase activity. Moreover, APAP administration significantly increased MDA, protein carbonylation, GSSG level, intracellular ROS production and cytochrome P450 enzyme (CYPP450) activity. The same exposure decreased GSH level, ferric reducing/antioxidant power (FRAP) as well as the activities of antioxidant enzymes indicating that APAP-induced renal damage was mediated through oxidative stress. Besides, APAP exposure significantly reduced mitochondrial membrane potential and induced up-regulation of CYP2E1 in renal tissues although JNK did not play any significant role in this APAP-induced renal pathophysiology. Caspase 9/3 immunoblot and DNA fragmentation analyses showed that APAP-induced renal cell damage was mostly necrotic in nature, although some apoptosis also occurred simultaneously. Taurine treatment both pre and post (150 mg/kg body weight for 3 days, orally) to APAP exposure, however, significantly reduced APAP-induced nephrotoxicity through its antioxidant properties, urinary excretion of APAP and suppression of CYP2E1. Results suggest that taurine might be a potential therapeutic candidate against APAP-induced acute nephrotoxicity.
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PMID:Taurine protects acetaminophen-induced oxidative damage in mice kidney through APAP urinary excretion and CYP2E1 inactivation. 2006 17

Our study aimed at investigating the influence of elevated atmospheric CO(2) concentration on the salinity tolerance of the cash crop halophyte Aster tripolium L., thereby focussing on protein expression and enzyme activities. The plants were grown in hydroponics using a nutrient solution with or without addition of NaCl (75% seawater salinity), under ambient (380 ppm) and elevated (520 ppm) CO(2). Under ambient CO(2) concentration enhanced expressions and activities of the antioxidant enzymes superoxide dismutase, ascorbate peroxidase, and glutathione-S-transferase in the salt-treatments were recorded as a reaction to oxidative stress. Elevated CO(2) led to significantly higher enzyme expressions and activities in the salt-treatments, so that reactive oxygen species could be detoxified more effectively. Furthermore, the expression of a protective heat shock protein (class 20) increased under salinity and was even further enhanced under elevated CO(2) concentration. Additional energy had to be provided for the mechanisms mentioned above, which was indicated by the increased expression of a beta ATPase subunit and higher v-, p- and f-ATPase activities under salinity. The higher ATPase expression and activities also enable a more efficient ion transport and compartmentation for the maintenance of ion homeostasis. We conclude that elevated CO(2) concentration is able to improve the survival of A. tripolium under salinity because more energy is provided for the synthesis and enhanced activity of enzymes and proteins which enable a more efficient ROS detoxification and ion compartmentation/transport.
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PMID:Elevated atmospheric CO2 concentration enhances salinity tolerance in Aster tripolium L. 2007 26


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