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:1.6.99.5 (NADH dehydrogenase)
2,135 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enzymes of mitochondrial respiratory chain, NADH dehydrogenase (complex I) and cytochrome c oxidase (complex IV), were completely inhibited by 6-hydroxydopamine with IC50 = 10.5 microM and IC50 = 34 microM respectively. The enzyme inhibition was insensitive to the change of NADH or cytochrome c concentrations. The extent of complex I inhibition decreased as a consequence of both non-enzymatic and monoamine oxidase-catalyzed oxidation of 6-hydroxydopamine. Monoamine oxidase A and B inhibitors, tranylcypromine and clorgyline but not l-deprenyl increased the extent of 6-hydroxydopamine induced inhibition of complex I. Thus, 6-hydroxydopamine itself and not its oxidation products may be responsible for the neurotoxicity of this agent via inhibition of respiratory chain enzymes.
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PMID:Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine. 779 73

The expression of both mitochondrial and nuclear genes encoding enzymes involved in electron transport and oxidative phosphorylation was examined in bovine cardiac tissue during early growth, development and aging. The steady state level of mRNAs for mitochondrial genes including ATPase 6. COXII and cyt b increased 2.5-4-fold relative to early fetal levels in late fetal and young adult tissues and showed a marked decline (30-50%) in older adult tissues. Similar results were found with the nuclear genes, COXVB and ATP-beta synthase showing coordinate regulation of the two genomes. An increase in mtDNA copy number correlated with the increase in transcript level. Enzyme activity levels for NADH dehydrogenase and cytochrome c oxidase showed a similar trend, albeit of lesser magnitude. These activity levels contrasted with the activity level of an entirely nuclear-encoded mitochondrial enzyme, citrate synthase, which increased not only throughout development but in the older adult tissue. This study indicates that there is a pattern of increasing mitochondrial and nuclear gene expression for OXPHOS enzymes in developing cardiac tissue and decreasing OXPHOS gene expression in the aging heart.
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PMID:Mitochondrial gene expression during bovine cardiac growth and development. 779 43

Chloroquine causes an increase in phospholipid and a decrease in cholesterol in liver mitochondria. A significant decrease in the activities of mitochondrial inner membrane enzymes such as NADH dehydrogenase, succinate dehydrogenase and cytochrome c oxidase is observed. Decrease in cytochrome contents and respiratory control ratio, shown by a decrease in state 3(+ADP) and an increase in state 4 (-ADP), implies decreased ATP synthesis following chloroquine administration. The results confirm drug-induced inhibition of mitochondrial respiration, thereby impairing availability and utilisation of energy.
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PMID:Effect of chloroquine on rat liver mitochondria. 789 9

The objective of this study was to explore the possible cause(s) underlying the previously observed, age-related increase in the rate of mitochondrial H2O2 release in the housefly. The hypothesis that an imbalance between different respiratory complexes may be a causal factor was tested. Cytochrome c oxidase activity was found to sharply decline in the latter part of the life span of the flies. Effects of different substrates and respiratory inhibitors were determined in order to ascertain if a decrease in cytochrome c oxidase activity could be responsible for the increased H2O2 release. H2O2 was measured spectrofluorometrically using horseradish peroxidase and p-hydroxphenylacetate as an indicator. Neither NADH-linked substrates nor succinate caused a stimulation of H2O2 production. H2O2 release by mitochondria, inhibited with rotenone and antimycin A, was greatly increased upon supplementation with alpha-glycerophosphate; however, the further addition of KCN or myxothiazol, to such preparations, caused a depression of H2O2 generation. In contrast, relatively low concentrations of KCN or myxothiazol were found to stimulate H2O2 release in insect mitochondria supplemented with alpha-glycerophosphate and exposed to rotenone, but not antimycin A. Results are interpreted to suggest that partial inhibition of cytochrome c oxidase activity can lead to the stimulation of mitochondrial H2O2 production in the housefly at site(s) other than NADH dehydrogenase and ubisemiquinone/cytochrome b region; a possible source may be glycerophosphate dehydrogenase.
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PMID:Aging, cytochrome oxidase activity, and hydrogen peroxide release by mitochondria. 839 19

Previous in vitro studies have shown that isolated mitochondria can generate oxygen radicals. However, whether a similar phenomenon can also occur in intact organs is unknown. In the present study, we tested the hypothesis that resumption of mitochondrial respiration upon reperfusion might be a mechanism of oxygen radical formation in postischemic hearts, and that treatment with inhibitors of mitochondrial respiration might prevent this phenomenon. Three groups of Langendorff-perfused rabbit hearts were subjected to 30 min of global ischemia at 37 degrees C, followed by reflow. Throughout ischemia and early reperfusion the hearts received, respectively: (a) 5 mM KCl (controls), (b) 5 mM sodium amobarbital (Amytal, which blocks mitochondrial respiration at Site I, at the level of NADH dehydrogenase), and (c) 5 mM potassium cyanide (to block mitochondrial respiration distally, at the level of cytochrome c oxidase). The hearts were then processed to directly evaluate oxygen radical generation by electron paramagnetic resonance spectroscopy, or to measure oxygen radical-induced membrane lipid peroxidation by malonyl dialdehyde (MDA) content of subcellular fractions. Severity of ischemia, as assessed by 31P-nuclear magnetic resonance measurements of cardiac ATP, phosphocreatine, and pH, was similar in all groups. Oxygen-centered free radical concentration averaged 3.84 +/- 0.54 microM in reperfused control hearts, and it was significantly reduced by Amytal treatment (1.98 +/- 0.26; p < 0.05), but not by KCN (2.58 +/- 0.96 microM; p = not significant (NS)), consistent with oxygen radicals being formed in the mitochondrial respiratory chain at Site I. Membrane lipid peroxidation of reperfused hearts was also reduced by treatment with Amytal, but not with KCN. MDA content of the mitochondrial fraction averaged 0.75 +/- 0.06 nM/mg protein in controls, 0.72 +/- 0.06 in KCN-treated hearts, and 0.54 +/- 0.05 in Amytal-treated hearts (p < 0.05 versus both groups). Similarly, MDA content of lysosomal membrane fraction was 0.64 +/- 0.09 nM/mg protein in controls, 0.79 +/- 0.15 in KCN-treated hearts, and 0.43 +/- 0.06 in Amytal-treated hearts (p < 0.05 versus both groups). Since the effects of Amytal are known to be reversible, in a second series of experiments we investigated whether transient mitochondrial inhibition during the initial 10 min of reperfusion was also associated with beneficial effects on subsequent recovery of cardiac function after wash-out of the drug. At the end of the experiment, recovery of left ventricular end-diastolic and of developed pressure was significantly greater in those hearts that had been treated with Amytal during ischemia and early reflow, as compared to untreated hearts.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow. 839 7

The possible role of calmodulin in mitochondrial functions was investigated in Ehrlich ascites tumor cell and mouse liver mitochondria employing sulfonamide compounds as calmodulin indicators. N-[6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide (W7), the most potent of the sulfonamide compounds, inhibited mitochondrial protein synthesis and oxidative phosphorylation. The inhibitors had no significant effect on mitochondrial cytochrome c oxidase, oligomycin-sensitive ATPase and NADH dehydrogenase activities. Depletion of endogenous ATP pool seemed to be the main mechanism of inhibition of mitochondrial translation by sulfonamides. The results also show that mitochondria from hepatic tissues are relatively less sensitive to sulfonamide drugs as compared to the Ehrlich ascites tumor cell mitochondria. Results of Ca2+ autoradiography revealed 2-3-fold higher levels of calmodulin-like Ca2+ binding protein in extracts from Ehrlich ascites tumor cell mitoplasts as compared to mitoplasts from mouse liver. These results suggest cell and tissue specific variations in Ca(2+)-dependent processes in the mitochondrial compartment.
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PMID:Inhibition of mitochondrial translation by calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide. 849 53

The mitochondria harvested at the end of perfusion of control hearts and assayed for respiratory activity had a better function after ischemia and reperfusion following trimetazidine injection when glutamate was used as substrate. The protective effect of trimetazidine was enhanced when the mitochondria were isolated from hypertrophied perfused rat hearts. In fact the drug improved both the RCI and QO2 parameters with glutamate or succinate as substrates and raised the glutamate-induced QO2 value of mitochondria extracted from the hypertrophied heart perfused in aerobic conditions. In the aerobically perfused heart trimetazidine did not change either the levels of tissue malondialdehyde and lipofuscin, or the rate of mitochondrial O.2 generation while it reduced the O.2 formation and malondialdehyde content in the hypertrophied heart. After ischemia and reperfusion, the drug reproduced these protective effects in the hypertrophied hearts and reduced the level of tissue malondialdehyde in control hearts. The protective effect of trimetazidine against MDA formation was dose-dependent, being more evident at a higher dose (10 mumol/l). Preincubation of rat heart mitochondria with 0.1-10 mumol/l trimetazidine did not affect NADH oxidase, NADH dehydrogenase and NADH-cytochrome c reductase, succinate oxidase and cytochrome c oxidase activities. These results indicate that trimetazidine injected into isolated rat hearts protects against the damage induced on cardiac energetics and oxidative injuries by moderate ischemia and reperfusion stress, particularly in monocrotaline-induced hypertrophy in the rat heart. We suggest that trimetazidine reduces the formation of oxidative damage by preserving cardiac mitochondrial function.
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PMID:Effect of trimetazidine on mitochondrial function and oxidative damage during reperfusion of ischemic hypertrophied rat myocardium. 851 81

The complete 27,694-bp mitochondrial (mt) DNA sequence of Hansenula wingei, which is a typical budding yeast and contains circular mitochondrial DNA, has been determined. The mt sequence contains genes encoding large and small ribosomal RNAs, 25 tRNAs, three subunits of cytochrome c oxidase (subunits 1, 2 and 3), three subunits of ATPase (subunits 6, 8 and 9), apocytochrome b, seven subunits of NADH dehydrogenase (subunits 1, 2, 3, 4, 4L, 5 and 6), and a ribosomal protein, VAR1. The VAR1 gene is considered to be a typical yeast type. This is consistent with data on DNA and the deduced amino-acid sequence homology comparisons of genes ubiquitous in yeast and fungi. However, we have identified seven genes encoding NADH dehydrogenase subunits, which are not found in other yeast mitochondrial genomes, thus placing the H. wingei mitochondrial genome in a unique position. In addition the H. wingei mitochondrial genome also encodes one tRNA pseudogene and one short unidentified ORF. The genome is compact with only two introns both of which contain an ORF. One intron lies in the large rRNA gene while the other is situated in the cytochrome c oxidase subunit-1 gene. The conserved nonanucleotide motif (A/T)TATAAG (T/A)(A/T), which is a transcription start signal in Saccharomyces cerevisiae mitochondria, has also been found in the H. wingei mitochondrial genome. The codon assignments for ATA and CTN in H. wingei mitochondria are different from those in S. cerevisiae mitochondria. These results indicate a unique and novel structure for the H. wingei mitochondrial genome in terms of characteristics which are typical for both yeast and for filamentous fungi. This is the first complete mt DNA sequence report in yeast.
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PMID:The complete mitochondrial DNA sequence of Hansenula wingei reveals new characteristics of yeast mitochondria. 853 12

The drug-resistant leukemic cell lines, CEM/VLB100 and K/DAU600, are more sensitive to tumor necrosis factor alpha (TNFalpha)-mediated cytotoxicity compared with their parental cell lines, CCRF-CEM and K562 cl.6. Drug-resistant leukemic cell lines have more active mitochondrial function, which is associated with a greater susceptibility to TNFalpha-induced respiratory inhibition. TNFalpha blocked electron transfer at three sites, NADH dehydrogenase (complex I), succinate dehydrogenase (complex II), and cytochrome c oxidase (complex IV). Respiratory rate and electron transport chain enzyme activities were significantly inhibited in the drug-resistant, TNF-sensitive cell lines. Respiratory inhibition preceded cell death by at least 5 to 8 hours. The respiratory failure was not compensated for by appropriate up-regulation of the glycolytic pathway. Increasing mitochondrial respiratory rate and enzyme activities by long-term culture with 2 mmol/L adenosine 5'-diphosphate (ADP) and Pi sensitized both drug-sensitive and drug-resistant cells to TNFalpha-induced cytolysis. Intramitochondrial free radicals generated by paraquat only had a limited and delayed effect on respiratory inhibition and cytolysis in comparison with the effect of TNFalpha. We conclude that TNFalpha-induced cytotoxicity in leukemic cells is, at least in part, mediated by inhibition of mitochondrial respiration. Free radical generation by TNFalpha may not directly lead to the observed inhibition of the mitochondrial electron transport and other mechanisms must be involved.
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PMID:Increased activity and sensitivity of mitochondrial respiratory enzymes to tumor necrosis factor alpha-mediated inhibition is associated with increased cytotoxicity in drug-resistant leukemic cell lines. 863 Apr 4

Five goat latissimus dorsi muscles (LDM) were submitted to a progressive chronic electrostimulation program to reach an integrated understanding of the fast-to-slow transformation process in large mammals. LDM were regularly sampled and followed during a period of 8 months. Each sample was simultaneously assessed for histoenzymological study, myosin and LDH isoforms and bioenergetic capacities [NADH dehydrogenase cytochrome c oxidoreductase (NADH Cyt c OR), succinate dehydrogenase cytochrome c oxidoreductase (Succ Cyt c OR), cytochrome c oxidase (Cyt c Ox) and LDH]. Such muscles were also tested with and without completion of II to I transformation for their mechanical properties in isometric and isotonic strain gauge testing. The conversion of fast-to-slow myosin monitored by heavy chain (HC I) and light chain slow component (LC2s) began a few days after stimulation and was almost 100% after 100 days. The H-LDH isoforms evolved similarly but did not reach 100% conversion after 200 days. The activity of respiratory chain oxidases increased within 36 h but to a variable extent and peaked after 32 days, corresponding to a 75% transformation of myosin compared to initial levels. NADH Cyt c OR, Succ Cyt c OR, and Cyt c Ox, respectively increased 10-, 5- and 5-fold. These activities then significantly decreased before the completion of the myofibrillar transformation and reached a plateau with stable activities that remained 2- to 3-fold higher than the unstimulated LDM. LDH activity sharply decreased until day 62 (5-fold) and then plateaued. Functionally, muscle showed a reduced speed of contraction and moderate reduction in power output but had become fatigue-resistant. This study documents the transformation process in large mammals and suggests the dynamic relation between workload, aerobic-anaerobic metabolism and the contractile myofibrillar system.
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PMID:Type II to type I transformation of chronically stimulated goat latissimus dorsi muscle: a histoenzymological, biochemical, bioenergetic, and functional study. 883 65


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