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)

Previous studies from our laboratory have shown that mitochondrial dysfunction may be an important early event in S-[(1 and 2)-phenyl-2-hydroxyethyl]cysteine (PHEC)-induced cytotoxicity in isolated rat renal proximal tubules. The present study has therefore examined in more detail PHEC-induced mitochondrial dysfunction, both in vivo and in vitro, using isolated renal cortical mitochondria. Renal cortical mitochondria isolated from PHEC-treated rats in vivo showed depressed effects on the mitochondrial respiration and oxidative phosphorylation in both a dose (0, 250, and 500 micromol/kg iv)- and time (0-24 h)-dependent manner in the presence of both succinate (Site 2) and malate plus alpha-ketoglutarate (Site 1) as respiratory substrates, with initial significant depression occurring as early as 4 h following treatment with 500 micromol PHEC/kg. Similar mitochondrial dysfunctions were observed in vitro in concentration- and time-dependent manners with both respiratory substrates. PHEC also caused a marked dose-dependent inhibition of mitochondrial succinate dehydrogenase and NADH cytochrome c reductase activities both in vivo and in vitro, with initial inhibition occurring as early as 4 h after in vivo administration and 45 min after exposure to PHEC in vitro, while the NADH dehydrogenase activity was not considerably inhibited. The mitochondrial ATPase activity was significantly decreased 4 and 24 h following treatment with PHEC (500 micromol/kg). These results suggest that PHEC exerts its inhibitory effect on the mitochondrial respiration and oxidative phosphorylation through the action on the mitochondrial electron transport chain. PHEC significantly reduced the activity of adenine nucleotide translocase as well as the net uptake of substrates by mitochondria without affecting their efflux within 2-4 h after its injection (500 micromol/kg). On the other hand, significant renal damage, as assessed by morphological study, appeared as early as 24 h following such treatment. The observation of similar effects after both in vivo and in vitro exposures may suggest that the effect on mitochondria may have a pathogenic role in PHEC-induced renal injury in rats. PHEC produces mitochondrial toxicity that results from an inactivation of mitochondrial anionic substrate transporters as well as from an inhibition of activities of adenine nucleotide translocase and dehydrogenases.
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PMID:S-[(1 and 2)-phenyl-2-hydroxyethyl]cysteine-induced alterations in renal mitochondrial function in male Fischer-344 rats. 970 95

Two mechanisms may affect the yield of the oxidative phosphorylation pathway in isolated mitochondria: (i) a decrease in the intrinsic coupling of the proton pumps (H+/2e- or H+/ATP), and (ii) an increase in the inner membrane conductance (proton or cation leak). Hence three kinds of modifications can occur and each of them have been characterized in isolated rat liver mitochondria (see preceding chapter by Rigoulet et al.). In intact isolated hepatocytes, these modifications are linked to specific patterns of bioenergetic parameters, i.e. respiratory flux, mitochondrial redox potential, DY, and phosphate potential. (1) The increase in H+/ATP stoichiometry of the mitochondrial ATP synthase, as induced by almitrine [20], leads to a decrease in mitochondrial and cytosolic ATP/ADP ratios without any change in the protonmotive force nor in the respiratory rate or redox potential. (2) In comparison to carbohydrate, octanoate metabolism by beta-oxidation increases the proportion of electrons supplied at the second coupling site of the respiratory chain. This mimics a redox slipping. Octanoate addition results in an increased respiratory rate and mitochondrial NADH/NAD ratio while protonmotive force and phosphate potential are almost unaffected. The respiratory rate increase is associated with a decrease in the overall apparent thermodynamic driving force (2deltaE'o - ndeltap) which confirms the 'redox-slipping-like' effect. (3) An increase in proton conductance as induced by the protonophoric uncoupler 2,4-dinitrophenol (DNP) leads to a decrease, as expected, in the mitochondrial NADH/NAD and ATP/ ADP ratios and in deltapsi while respiratory rate is increased. Thus, each kind of modification (proton leak, respiratory chain redox slipping or increase in H+/ATP stoichiometry of ATPase) is related to a specific set of bioenergetic parameters in intact cells. Moreover, these patterns are in good agreement with the data found in isolated mitochondria. From this work, we conclude that quantitative analysis of four bioenergetic parameters (respiration rate, mitochondrial NADH/ NAD ratio, protonmotive force and mitochondrial phosphate potential) gives adequate tools to investigate the mechanism by which some alterations may affect the yield of the oxidative phosphorylation pathway in intact cells.
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PMID:Oxidative phosphorylation in intact hepatocytes: quantitative characterization of the mechanisms of change in efficiency and cellular consequences. 974 12

As a first step towards using cross-species comparison to complete the inventory of the nuclear genes that encode mitochondrial polypeptides, and ultimately to understand their function through systematic molecular and genetic analysis in a model organism of choice, we report here the characterization of 41 Drosophila melanogaster cDNAs. These cDNAs were isolated by screening an ovarian expression library with antibodies against mitochondrial proteins and identify 17 novel Drosophila genes. The deduced amino acid sequences encoded by the majority of these cDNAs turned out to show significant homology to mitochondrial proteins previously identified in other species. Among others, ORFs putatively encoding six different subunits of ATP synthase and three NADH:ubiquinone reductase subunits were detected. By in situ hybridization, all cDNAs were mapped to single bands on polytene chromosomes, thus identifying candidate Drosophila genes required for mitochondrial biogenesis and maintenance. A search of the Human Gene Index database made it possible in most cases to align the entire Drosophila coding sequence with a human consensus sequence, suggesting that the cDNAs originate from insect counterparts of expressed mammalian genes. Our experimental strategy represents an efficient approach to the identification and interspecies comparison of genes encoding products targeted to the mitochondrion.
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PMID:Identification of nuclear genes encoding mitochondrial proteins: isolation of a collection of D. melanogaster cDNAs homologous to sequences in the Human Gene Index database. 1007 Dec 11

The effects of the anti-inflammatory drugs diclofenac, piroxicam, indomethacin, naproxen, nabumetone, nimesulide, and meloxicam on mitochondrial respiration, ATP synthesis, and membrane potential were determined. Except for nabumetone and naproxen, the other drugs stimulated basal and uncoupled respiration, inhibited ATP synthesis, and collapsed membrane potential in mitochondria incubated in the presence of either glutamate + malate or succinate. Plots of membrane potential versus ATP synthesis (or respiration) showed proportional variations in both parameters, induced by different concentrations of nimesulide, meloxicam, piroxicam, or indomethacin, but not by diclofenac. The activity of the adenine nucleotide translocase was blocked by diclofenac and nimesulide; diclofenac also slightly inhibited mitochondrial ATPase activity. Naproxen did not affect any of the mitochondrial parameters measured. Nabumetone inhibited respiration, ATP synthesis, and membrane potential in the presence of glutamate + malate, but not with succinate. NADH oxidation in submitochondrial particles also was inhibited by nabumetone. Nabumetone inhibited O2 uptake in intact cells and in whole heart, whereas the other five drugs stimulated respiration. These observations revealed that in situ mitochondria are an accessible target. Except for diclofenac, a negative inotropic effect on cardiac contractility was induced by the drugs. The data indicated that nimesulide, meloxicam, piroxicam, and indomethacin behaved as mitochondrial uncouplers, whereas nabumetone exerted a specific inhibition of site 1 of the respiratory chain. Diclofenac was an uncoupler too, but it also affected the adenine nucleotide translocase and the H+-ATPase.
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PMID:Inhibition and uncoupling of oxidative phosphorylation by nonsteroidal anti-inflammatory drugs: study in mitochondria, submitochondrial particles, cells, and whole heart. 1007 80

Purification of mitochondria and mitochondrial protein complexes from green tissues is often severely impaired by the presence of chloroplasts and their proteins. Here we present a method which allows analysis of respiratory protein complexes from potato leaves. The procedure includes the preparation of an organellar fraction specifically enriched in mitochondria and the separation of organellar protein complexes by blue-native polyacrylamide gel electrophoresis (BN-PAGE). For the first time mitochondrial and chloroplast protein complexes have been resolved simultaneously in a native gel. BN-PAGE allowed the separation of eleven bands, including the mitochondrial NADH-dehydrogenase, the bc1 complex and the mitochondrial F1-ATP synthase as well as the chloroplast F1-ATP synthase, the cytochrome b6f complex, the two photosystems and the light harvesting complex. The resolution of the protein complexes in the first dimension was good enough to allow identification of all subunits of individual complexes in the second dimension under denaturing conditions. Thus, BN-PAGE offers an opportunity to analyze mitochondrial and chloroplast protein complexes from a single preparation from very small amounts of tissue. The implications of our findings, for studies on protein expression and turnover in different tissues and developmental stages, are discussed.
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PMID:Resolution of mitochondrial and chloroplast membrane protein complexes from green leaves of potato on blue-native polyacrylamide gels. 1098 14

Mitochondrial adenosine triphosphate (ATP) generation plays a major role in insulin secretion in pancreatic islet beta cells. The relationship between age and nutritional status of the islet and mitochondrial gene messenger RNA (mRNA) expression was investigated. Three animal groups were studied: infant (12-day-old) rats fed either mother's milk or a high carbohydrate (HC) diet; young (2 to 4-month-old) rats; and old (12 to 14-month-old) rats. The expression of mitochondrial cytochrome oxidase (CYO) (subunits I, II, and III), beta-nicotinamide adenine dinucleotide, reduced form dehydrogenase subunit 4 (NADH-DH4), and ATP synthase (subunit 6) (ATP-SYN6) mRNAs was characterized by semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR). The mitochondrial gene mRNAs were identified in each of the groups of rat islets and in RINm5F cells. CYO-II mRNA expression in young and old rat pancreatic islets was 12.7- and 8.2-fold higher, respectively, compared with the level in infant rat islets. The expression of NADH-DH4 and ATP-SYN6 mRNAs was 47% and 40% lower, respectively, in young rat islets compared with the level in infant rat islets. CYO-I, CYO-III, and cytoplasmic glyceraldehyde-3-phosphate dehydrogenase (GPDH) mRNA expression did not differ between experimental groups. Artificial rearing of infant rat pups on a HC diet for 8 days lead to a 3.3-fold increase in islet CYO-II mRNA expression compared with mother-fed pups. However, glucose (11 mmol/L) stimulation of cultured isolated islets from young and old rats for 4 days failed to affect the expression level of mitochondrial gene mRNAs. Thus, aging affected the differential expression of CYO-II, NADH-DH4, and ATP-SYN6 mRNAs in rat islets. CYO-II mRNA expression was modulated only in infant rat islets after in vivo administration of carbohydrate.
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PMID:Mitochondrial-encoded gene regulation in rat pancreatic islets. 1122 30

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease affecting approximately1% of the population older than 50 years. There is a worldwide increase in disease prevalence due to the increasing age of human populations. A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease. Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons.
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PMID:Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson's disease. 1135 Nov 30

The membrane fraction of Bacillus subtilis catalyzes the reduction of fumarate to succinate by NADH. The activity is inhibited by low concentrations of 2-(heptyl)-4-hydroxyquinoline-N-oxide (HOQNO), an inhibitor of succinate: quinone reductase. In sdh or aro mutant strains, which lack succinate dehydrogenase or menaquinone, respectively, the activity of fumarate reduction by NADH was missing. In resting cells fumarate reduction required glycerol or glucose as the electron donor, which presumably supply NADH for fumarate reduction. Thus in the bacteria, fumarate reduction by NADH is catalyzed by an electron transport chain consisting of NADH dehydrogenase (NADH:menaquinone reductase), menaquinone, and succinate dehydrogenase operating in the reverse direction (menaquinol:fumarate reductase). Poor anaerobic growth of B. subtilis was observed when fumarate was present. The fumarate reduction catalyzed by the bacteria in the presence of glycerol or glucose was not inhibited by the protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) or by membrane disruption, in contrast to succinate oxidation by O2. Fumarate reduction caused the uptake by the bacteria of the tetraphenyphosphonium cation (TPP+) which was released after fumarate had been consumed. TPP+ uptake was prevented by the presence of CCCP or HOQNO, but not by N,N'-dicyclohexylcarbodiimide, an inhibitor of ATP synthase. From the TPP+ uptake the electrochemical potential generated by fumarate reduction was calculated (Deltapsi = -132 mV) which was comparable to that generated by glucose oxidation with O2 (Deltapsi = -120 mV). The Deltapsi generated by fumarate reduction is suggested to stem from menaquinol:fumarate reductase functioning in a redox half-loop.
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PMID:Generation of a proton potential by succinate dehydrogenase of Bacillus subtilis functioning as a fumarate reductase. 1135 26

The growth and development of Caenorhabditis elegans are energy-dependent and rely on the mitochondrial respiratory chain (MRC) as the major source of ATP. The MRC is composed of approximately 70 nuclear and 12 mitochondrial gene products. Complexes I and V are multisubunit proteins of the MRC. The nuo-1 gene encodes the NADH- and FMN-binding subunit of complex I, the NADH-ubiquinone oxidoreductase. The atp-2 gene encodes the active-site subunit of complex V, the ATP synthase. The nuo-1(ua1) and atp-2(ua2) mutations are both lethal. They result in developmental arrest at the third larval stage (L3), arrest of gonad development at the second larval stage (L2), and impaired mobility, pharyngeal pumping, and defecation. Surprisingly, the nuo-1 and atp-2 mutations significantly lengthen the life spans of the arrested animals. When MRC biogenesis is blocked by chloramphenicol or doxycycline (inhibitors of mitochondrial translation), a quantitative and homogeneous developmental arrest as L3 larvae also results. The common phenotype induced by the mutations and drugs suggests that the L3-to-L4 transition may involve an energy-sensing developmental checkpoint. Since approximately 200 gene products are needed for MRC assembly and mtDNA replication, transcription, and translation, we predict that L3 arrest will be characteristic of mutations in these genes.
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PMID:Mitochondrial respiratory chain deficiency in Caenorhabditis elegans results in developmental arrest and increased life span. 1141 May 94

The ratios of the oxidative phosphorylation complexes NADH:ubiquinone reductase (complex I), succinate:ubiquinone reductase (complex II), ubiquinol:cytochrome c reductase (complex III), cytochrome c oxidase (complex IV), and F1F0-ATP synthase (complex V) from bovine heart mitochondria were determined by applying three novel and independent approaches that gave consistent results: 1) a spectrophotometric-enzymatic assay making use of differential solubilization of complexes II and III and parallel assays of spectra and catalytic activities in the samples before and after ultracentrifugation were used for the determination of the ratios of complexes II, III, and IV; 2) an electrophoretic-densitometric approach using two-dimensional electrophoresis (blue native-polyacrylamide gel electrophoresis and SDS-polyacrylamide gel electrophoresis) and Coomassie blue-staining indices of subunits of complexes was used for determining the ratios of complexes I, III, IV, and V; and 3) two electrophoretic-densitometric approaches that are independent of the use of staining indices were used for determining the ratio of complexes I and III. For complexes I, II, III, IV, and V in bovine heart mitochondria, a ratio 1.1 +/- 0.2:1.3 +/- 0.1:3:6.7 +/- 0.8:3.5 +/- 0.2 was determined.
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PMID:The ratio of oxidative phosphorylation complexes I-V in bovine heart mitochondria and the composition of respiratory chain supercomplexes. 1148 15


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