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)

Membrane vesicles of Escherichia coli prepared by osmotic lysis of lysozyme ethylenediaminetetracetate (EDTA) spheroplasts have approximately 60% of the total membrane-bound reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase (ED 1.6.99.3) and Mg2+-adenosine triphosphatase (ATPase) (EC 3.6.1.3) activities exposed on the outer surface of the inner membrane. Absorption of these vesicles with antiserum prepared against the purified soluble Mg2+-ATPase resulted in agglutination of approximately 95% of the inner membrane vesicles, as determined by dehydrogenase activity, and about 50% of the total membrane protein. The unagglutinated vesicles lacked all dehydrogenase activity and may consist of outer membrane. Lysozyme-EDTA vesicles actively transported calcium ion, using either NADH or adenosine 5'-triphosphate (ATP) as energy source. However, neither D-lactate nor reduced phenazine methosulfate energized calcium uptake, suggesting that the observed calcium uptake was not due to a small population of everted vesicles. Transport of calcium driven by either NADH or ATP was inhibited by simultaneous addition of D-lactate or reduced phenazine methosulfate. Proline transport driven by D-lactate oxidation was inhibited by either NADH oxidation or ATP hydrolysis. These results suggest that the portion of the total population of vesicles capable of active transport, i.e., the inner membrane vesicles, are functionally a homogeneous population but cannot be categorized as either right-side-out or everted, since activities normally associated with only one side of the inner membrane can be found on both sides of the membrane of these vesicles. Moreover, the data indicate that oxidation of NADH or hydrolysis of ATP by externally localized NADH dehydrogenase or Mg2+-ATPase establishes a protonmotive force of the opposite polarity from that established through D-lactate oxidation.
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PMID:Functional mosaicism of membrane proteins in vesicles of Escherichia coli. 19 Feb 12

Mitochondrial respiration, succinate dehydrogenase coenzyme Q reductase, and myosin B were investigated in ischemic myocardium from experimental myocardial infarction in dogs. Respiratory control ratio of mitochondria was impaired by ischemia at 60 min after coronary ligation, and oxygen consumption was inhibited 120 min later. Enzyme activity of succinate dehydrogenase coenzyme Q reductase was decreased at 6 hr after coronary ligation. Calcium ion sensitivity of myosin B declined 12 hr after coronary ligation. However, adenosine triphosphatase activity of myosin A from infarcted myocardium was not different from that of the intact one. These results suggest that interaction in the sequence of enzyme complexes was first impaired in ischemic myocardium and that deterioration of enzyme activity was then manifested.
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PMID:Relationship between energy liberation and utilization in ischemic cardiac muscle. 103 51

A study was undertaken to determine if cis-DDP and its second generation derivatives produced effects on mouse liver mitochondria, and if any of the observed effects could be correlated with the nephrotoxicity of the drugs. Although changes were observed in mitochondrial morphology, enzyme activity, Ca2+ influx, terbium binding and surface potential, no specific effect was correlated with nephrotoxicity. cis-DDP produced marked changes in mitochondrial morphology; electron probe analysis showed binding of the drug to the mitochondria. Inhibition of complex I and II activity of the respiratory chain and an ionic-strength-dependent effect on Tb3+ (a Ca2+ analogue) fluorescence were observed. The non-nephrotoxic derivatives, CHIP and tetraplatin, also produced significant changes in morphology. Treatment with these derivatives also produced decreases in mitochondrial enzyme activity, but the effect on terbium binding had an ionic-strength dependence which was inverse to that observed with cis-DDP. The tetravalent compounds also had a notable effect on mitochondrial surface potential. Carboplatin had an effect on morphology and Ca2+ influx and it inhibited the respiratory enzymes, although in a manner different from that observed with cis-DDP. Carboplatin had a minimal effect on terbium binding. It is evident that if the platinum drugs enter a cell to exert their action at the nuclear level, they will also depress mitochondrial function. The observed effects did not correlate with nephrotoxicity but, since all four compounds significantly altered mitochondrial structure and function, they may be related to the cytotoxicity of the drug.
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PMID:The interaction of platinum antitumour drugs with mouse liver mitochondria. 131 66

Manganese is known to accumulate in mitochondria and in mitochondria-rich tissues in vivo. Although Ca2+ enhances mitochondrial Mn2+ uptake, ATP-bound Mn2+ is not sequestered by suspended rat brain mitochondria, and ATP binds Mn2+ even more tightly than it binds Mg2+. Physiological levels of the polyamine spermine enhanced 54 Mn2+ uptake at the low [Ca2+]s characteristic of unstimulated cells (approximately 100 nM). With succinate as substrate, Mn2+ inhibited oxygen consumption by suspensions of rat liver mitochondria after the addition of ADP but not after the addition of uncoupler. With glutamate/malate as substrate, Mn2+ inhibited ADP-stimulated respiration and also slightly inhibited uncoupler-stimulated respiration. State 4 (resting) respiration was unchanged in all cases, indicating that the inner membrane retained its impermeability to protons. These results suggest that Mn2+ was not oxidized and that it can interfere directly with oxidative phosphorylation, most likely by binding to the F1 ATPase. Mn2+ may also bind to the NADH dehydrogenase complex, but not strongly enough to affect electron transport in vivo. It is suggested that accumulation of manganese within the mitochondria of globus pallidus may help explain the distinctive pathology of manganism.
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PMID:Mn2+ sequestration by mitochondria and inhibition of oxidative phosphorylation. 163 87

Both the external oxidation of NADH and NADPH in intact potato (Solanum tuberosum L. cv. Bintje) tuber mitochondria and the rotenone-insensitive internal oxidation of NADPH by inside-out submitochondrial particles were dependent on Ca2+. The stimulation was not due to increased permeability of the inner mitochondrial membrane. Neither the membrane potential nor the latencies of NAD(+)-dependent and NADP(+)-dependent malate dehydrogenases were affected by the addition of Ca2+. The pH dependence and kinetics of Ca(2+)-dependent NADPH oxidation by inside-out submitochondrial particles were studied using three different electron acceptors: O2, duroquinone and ferricyanide. Ca2+ increased the activity with all acceptors with a maximum at neutral pH and an additional minor peak at pH 5.8 with O2 and duroquinone. Without Ca2+, the activity was maximal around pH 6. The Km for NADPH was decreased fourfold with ferricyanide and duroquinone, and twofold with O2 as acceptor, upon addition of Ca2+. The Vmax was not changed with ferricyanide as acceptor, but increased twofold with both duroquinone and O2. Half-maximal stimulation of the NADPH oxidation was found at 3 microM free Ca2+ with both O2 and duroquinone as acceptors. This is the first report of a membrane-bound enzyme inside the inner mitochondrial membrane which is directly dependent on micromolar concentrations of Ca2+. Mersalyl and dicumarol, two potent inhibitors of the external NADH dehydrogenase in plant mitochondria, were found to inhibit internal rotenone-insensitive NAD(P)H oxidation, at the same concentrations and in manners very similar to their effects on the external NAD(P)H oxidation.
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PMID:Effect of calcium ions and inhibitors on internal NAD(P)H dehydrogenases in plant mitochondria. 172 51

Slow active/inactive transition of the membrane-bound mitochondrial NADH-ubiquinone reductase (Kotlyar, A.B. and Vinogradov, A.D. (1990) Biochim. Biophys. Acta 1019, 151-158) is sensitive to Ca2+ and other divalent cations. Millimolar concentrations of Ca2+ drastically reduce the rate of the turnover-dependent activation of NADH-ubiquinone reductase. When NADH oxidase, the rotenone-sensitive NADH-ubiquinone reductase or the succinate-supported delta mu H+-dependent NAD+ reduction were initiated by the deactivated enzyme preparations all the three activities were strongly inhibited by Ca2+; no sensitivity of these reactions to Ca2+ was observed when the assays were started by the activated enzyme preparations. The affinity of the deactivated enzyme to polyvalent cations was in the following order: Ni2+ greater than Co2+ greater than La3+ greater than Mn2+ greater than Ca2+ approximately Mg2+ greater than Ba2+. Monovalent metal cations had no effect on the slow turnover-dependent enzyme activation. The apparent affinity of the deactivated enzyme to Ca2+ was strongly pH-dependent. The KCa2+ values of 5.7 mM and 0.6 mM at pH 7.5 and 8.5 were determined from the presteady-state kinetics parameters. The spontaneous temperature-dependent deactivation of the enzyme was insensitive to Ca2+. Ca2+ increases the reactivity of the enzyme sulfhydryl group in the deactivated preparations towards N-ethylmaleimide. This effect was also used to quantitate Ca2+ affinity for the enzyme. The KCa2+ values of 1.2 mM and 0.4 mM at pH 8.0 and 9.0, respectively, were determined. The data obtained suggest that Ca2+ content in the mitochondrial matrix may play an important role in the control of NADH oxidation by the respiratory chain.
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PMID:Effect of Ca2+ ions on the slow active/inactive transition of the mitochondrial NADH-ubiquinone reductase. 173 7

The 78-kDa glucose-regulated protein (GRP78) is ubiquitously expressed in many cell types. Its promoter contains multiple protein-binding sites and functional elements. In this study we examined a high affinity protein-binding site spanning bp -198 to -180 of the rat grp78 promoter, using nuclear extracts from both B-lymphoid and HeLa cells. This region contains a sequence TGACGTGA which, with the exception of one base, is identical to the cAMP-response element (CRE). Site-directed mutagenesis reveals that this sequence functions as a major basal level regulatory element in hamster fibroblast cells and is also necessary to maintain high promoter activity under stress-induced conditions. By gel mobility shift analysis, we detect two specific protein complexes. The major specific complex I, while immunologically distinct from the 42-kDa CRE-binding protein (CREB), binds most strongly to the grp site, but also exhibits affinity for the CRE consensus sequence. As such, complex I may consist of other members of the CREB/activating transcription factor protein family. The minor specific complex II consists of CREB or a protein antigenically related to it. A nonspecific complex III consists of the Ku autoantigen, an abundant 70- to 80-kDa protein complex in HeLa nuclear extracts. By cotransfection experiments, we demonstrate that in F9 teratocarcinoma cells, the grp78 promoter can be transactivated by the phosphorylated CREB or when the CREB-transfected cells are treated with the calcium ionophore A23187. The differential regulation of the grp78 gene by cAMP in specific cell types and tissues is discussed.
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PMID:A binding site for the cyclic adenosine 3',5'-monophosphate-response element-binding protein as a regulatory element in the grp78 promoter. 183 91

Reoxygenation of the hypoxic myocardium results in a number of processes, including an O2-dependent increase in total tissue Ca2+ and cell lysis in which mitochondrial electron transport plays a key role. In the present study we have isolated mitochondria from perfused rat hearts subjected to hypoxia and found no change in their respiratory function relative to controls. In contrast, mitochondria isolated immediately after reoxygenation of hypoxic-perfused hearts exhibited a specific and significant decrease in NADH:CoQ reductase (Complex I; EC 1.6.5.3) activity, as measured both polarographically and spectrophotometrically. Isolated cardiomyocytes subjected to a similar protocol of hypoxia/reoxygenation also exhibited a specific decrease in Complex I activity. Myocardial perfusion with media containing Ruthenium Red protected against the reoxygenation-dependent loss of Complex I activity. These observations taken together suggest that mitochondrial Ca2+ uptake on reoxygenation is implicated in the mechanism of the specific loss of Complex I activity.
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PMID:Reoxygenation-dependent decrease in mitochondrial NADH:CoQ reductase (Complex I) activity in the hypoxic/reoxygenated rat heart. 190 Apr 16

Zinc deficiency (ZD) is teratogenic in rats, and fetal skeletal defects are prominent. To elucidate further the effects of maternal ZD in the fetal skeleton, we performed a morphological and histochemical study of tibial growth plate (GP) in ZD rat fetuses. The histochemical study included the identification of calcium, of hydrolytic enzymes associated with the process of calcification, and of oxidative enzymes related to energy production and to the synthesis of proteoglycans. Pregnant Sprague-Dawley rats were fed (1) a control diet (76.4 micrograms Zn/g diet) ad libitum (group C), (2) a zinc-deficient diet (0 micrograms/g) ad libitum (group ZD), or (3) the control diet pair-fed to the ZD rats (group PF). On day 21 of gestation, laparotomies were performed, the fetuses were removed, and fetal tibiae obtained. Specimens were stained with hematoxylin-eosin (H&E) and Masson Trichrome and were processed for identification of alkaline phosphatase, adenosine triphosphatase, succinic dehydrogenase, NADH dehydrogenase, and calcium. The morphologic patterns found in ZD fetal tibiae indicated defects in various cell types implicated in bone metabolism. Staining for hydrolytic enzymes revealed alterations in the size and distribution of matrix vesicles and a weaker staining for ATPase in ZD fetuses. Staining for oxidative enzymes was overall more intense in ZD fetal tibiae. ZD fetuses also presented irregular and defective calcification. These findings indicate that severe maternal ZD in the rat results in structural and functional alterations in the GP of fetal bone, leading to a defective endochondral ossification.
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PMID:Changes in the fetal tibial growth plate secondary to maternal zinc deficiency in the rat: a histological and histochemical study. 196 89

Ischemia and reperfusion causes severe mitochondrial damage, including swelling and deposits of hydroxyapatite crystals in the mitochondrial matrix. These crystals are indicative of a massive influx of Ca2+ into the mitochondrial matrix occurring during reoxygenation. We have observed that mitochondria isolated from rat hearts after 90 minutes of anoxia followed by reoxygenation, show a specific inhibition in the electron transport chain between NADH dehydrogenase and ubiquinone in addition to becoming uncoupled (unable to generate ATP). This inhibition is associated with an increased H2O2 formation at the NADH dehydrogenase level in the presence of NADH dependent substrates. Control rat mitochondria exposed for 15 minutes to high Ca2+ (200 nmol/mg protein) also become uncoupled and electron transport inhibited between NADH dehydrogenase and ubiquinone, a lesion similar to that observed in post-ischemic mitochondria. This Ca(2+)-dependent effect is time dependent and may be partially prevented by albumin, suggesting that it may be due to phospholipase A2 activation, releasing fatty acids, leading to both inhibition of electron transport and uncoupling. Addition of arachidonic or linoleic acids to control rat heart mitochondria, inhibits electron transport between Complex I and III. These results are consistent with the following hypothesis: during ischemia, the intracellular energy content drops severely, affecting the cytoplasic concentration of ions such as Na+ and Ca2+. Upon reoxygenation, the mitochondrion is the only organelle capable of eliminating the excess cytoplasmic Ca2+ through an electrogenic process requiring oxygen (the low ATP concentration makes other ATP-dependent Ca2+ transport systems non-operational).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mitochondrial generation of oxygen radicals during reoxygenation of ischemic tissues. 206 Aug 40


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