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:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this paper, we report on our studies of the effects of MIBG, a structural analogue of norepinephrine, on SK-N-BE(2c) cells. In micromolar concentrations, MIBG caused almost complete inhibition of the proliferation of SK-N-BE(2c) cells. In intact SK-N-BE(2c) cells, addition of MIBG led to a decrease of the ATP to ADP ratio. A progressive increase of the lactate to pyruvate ratio (due to increased lactate production) was observed after incubation of the cells with glucose and increasing concentrations of MIBG. In cells treated with digitonin, MIBG inhibited malate driven ATP synthesis. Comparable inhibition of ATP synthesis with succinate as a substrate required higher concentrations of MIBG. These results indicate that, apart from inhibition of complex I, MIBG was capable of inhibiting at least one other complex of the respiratory chain. Although maximal inhibition of ATP synthesis was observed at a concentration of 10 microM, optimal inhibition of cell proliferation occurred at a MIBG concentration > 25 microM. This suggests that MIBG also influences other cellular processes apart from mitochondrial ATP synthesis, resulting in additional inhibition of cell proliferation.
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PMID:Meta-iodobenzylguanidine (MIBG) inhibits malate and succinate driven mitochondrial ATP synthesis in the human neuroblastoma cell line SK-N-BE(2c). 757 73

Studies from our laboratory have shown that short-term ethanol exposure inhibits epidermal growth factor-dependent replication of cultured fetal rat hepatocytes, along with a drop in ATP level, and that these effects could be caused, at least in part, by ethanol-induced oxidative stress. In these prior studies, mitochondrial morphology was abnormal and membrane lipid peroxidation products were increased, along with reduced transmembrane potential and enhanced permeability to sucrose. To define the effects of ethanol on mitochondrial function further, the present study examines the impact of ethanol exposure on mitochondrial electron transport chain components. A 24-hr exposure of cultured fetal rat hepatocytes to ethanol (2.5 mg/ml) reduced mitochondrial complex I activity by 16% (p < 0.05), complex IV by 28% (p < 0.05), and succinate dehydrogenase by 23% (p < 0.05). This reduction was paralleled by lower ADP translocase activity (24%, p < 0.05) and diminished mitochondrial glutathione (GSH) (20%, p < 0.05). Pretreatment with 0.1 mM S-adenosyl methionine, before ethanol exposure, normalized mitochondrial GSH along with activities of complex I, complex IV, and succinate dehydrogenase. A 3-hr exposure of isolated mitochondria (which do not metabolize ethanol) to ethanol (2.5 mg/ml), inhibited the activities of complex I (19%, p < 0.05), complex IV (24%, p < 0.05), and of ATP synthesis (20%, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of acute ethanol exposure on cultured fetal rat hepatocytes: relation to mitochondrial function. 769 41

Isolated mitochondria supplemented with succinate or NAD(+)-linked substrates generate hydrogen peroxide (H2O2) in State 4 and the generation is enhanced by antimycin A, an inhibitor of the respiratory chain. Superoxide is a stoichiometric precursor of mitochondrial H2O2 because the ratio of O2-/H2O2 generation rates is close to 2.0 and is generated by an autoxidizable component in the NADH dehydrogenase and the ubiquinone-cytochrome b site. Lipid peroxidation is a free radical-mediated degradation of polyunsaturated fatty acids. Lipid-peroxidation reactions by bovine submitochondrial particles are supported by NADH or NADPH in the presence of ADP-Fe3+ chelate. Electrons from NADH are supplied to the reactions from a component between the substrate site and the rotenone-sensitive site of the NADH dehydrogenase. The peroxidation is dependent on the rate of electron input into the respiratory chain and on the concentration of reduced ubiquinone. Alteration of inner-membrane components and damage to electron-transfer activities of submitochondrial particles are induced by lipid peroxidation. 1-Melhyl-4-phenylpyridinium (MPP+), a metabolite of a parkinsonism-inducing drug, induces NADH-dependent superoxide formation and enhances NADH-dependent lipid peroxidation in submitochondrial particles, indicating that the oxidative stress induced by MPP+ may potentiate its toxicity in dopamine neurons.
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PMID:[Superoxide formation and lipid peroxidation by the mitochondrial electron-transfer chain]. 777 32

The fatty acid concentration of each lipid fraction of plerocercoids of Spirometra erinacei and the host snake serum was investigated. The major fatty acids of phospholipid of the plerocercoids were C18:1, C18:0 and C16:0, and those of the host snake serum were C16:0, C18:1 and C18:0, in order of amount in both cases. The changes of the fatty acid composition of phospholipid of the plerocercoids when they were incubated in physiological saline at 18 degrees C and at 37 degrees C for 24 h were investigated in both cases. Polyunsaturated fatty acids increased at 18 degrees C, and saturated fatty acids increased at 37 degrees C. Michaelis constants (Km) of beta-hydroxyacyl-CoA dehydrogenase (HAD), NADH: ubiquinone oxidoreductase (complex I) (NADH: ferricyanide reaction) and complex I (NADH: ubiquinone reaction) for NADH were 20.6, 50 and 13.3 microM, respectively. The ATP production in mitochondria of the plerocercoids was accelerated by adding ADP and inhibited by adding such electron transport system inhibitors as rotenone, antimycin A and sodium cyanide. These results suggested that the fatty acids in the plerocercoids played an important role in regulating the fluidity of membrane by changing the composition in membrane lipid corresponding with the change of temperature circumstance. The NADH reduced by HAD might be accepted by the complex I in the electron transport system, and thus the parasites were capable of ATP production in a classical pathway of the oxidative phosphorylation system.
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PMID:The fatty acids of each lipid fraction and their use in providing energy source of the plerocercoid of Spirometra erinacei. 779 67

Dopamine, due to metabolism by monoamine oxidase or autoxidation, can generate toxic products such as hydrogen peroxide, oxygen-derived radicals, semiquinones, and quinones and thus exert its neurotoxic effects. Intracerebroventricular injection of dopamine into rats pretreated with the monoamine oxidase nonselective inhibitor pargyline caused mortality in a dose-dependent manner with LD50 = 90 micrograms. Norepinephrine was less effective with LD50 = 141 micrograms. The iron chelator desferrioxamine completely protected against dopamine-induced mortality. In the absence of pargyline more rats survived, indicating that the products of dopamine enzymatic metabolism are not the main contributors to dopamine-induced toxicity. Biochemical analysis of frontal cortex and striatum from rats that received a lethal dose of dopamine did not show any difference from control rats in lipid and protein peroxidation and glutathione reductase and peroxidase activities. Moreover, dopamine significantly reduced the formation of iron-induced malondialdehyde in vitro, thus suggesting that earlier events in cell damage are involved in dopamine toxicity. Indeed, dopamine inhibited mitochondrial NADH dehydrogenase activity with IC50 = 8 microM, and that of norepinephrine was twice as much (IC50 = 15 microM). Dopamine-induced inhibition of NADH dehydrogenase activity was only partially reversed by desferrioxamine, which had no effect on norepinephrine-induced inhibition. These results suggest that catecholamines can cause toxicity not only by inducing an oxidative stress state but also possibly through direct interaction with the mitochondrial electron transport system. The latter was further supported by the ability of ADP to reverse dopamine-induced inhibition of NADH dehydrogenase activity in a dose-dependent manner.
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PMID:Dopamine neurotoxicity: inhibition of mitochondrial respiration. 783 65

Physiological increases in matrix calcium are known to stimulate three mitochondrial dehydrogenases. In mitochondria isolated from rat heart, calcium stimulates rates of State 3 respiration during oxidation of succinate and of several NAD-linked substrates. In this study, we investigated the effects of calcium on NADH dehydrogenase and succinate dehydrogenase activities since the mechanism of these effects is unresolved. The respiratory activities of intact mitochondria and submitochondrial particles (SMP) were compared during incubation in media containing either ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA) or a Ca2+/EGTA buffer (approximately 1 microM free Ca2+). In intact mitochondria oxidizing 20 mM glutamate plus 2 mM malate, the membrane potential (delta psi) and matrix NAD(P)H were maintained at higher levels, and the maximal rate of ADP-stimulated respiration (State 3) was increased twofold by the presence of calcium. With succinate as substrate, calcium stimulated State 3 respiration but it did not influence the pyridine nucleotides redox state or membrane potential. Stimulation of succinate-supported respiration by addition of 6-10 microM ADP in the presence of hexokinase caused a sudden decrease in NAD(P)H and collapse of delta psi. This effect was not caused by inhibition of succinate dehydrogenase or by opening of the nonspecific pore. Calcium did not influence the oxidation of succinate by SMP containing either activated or nonactivated succinate dehydrogenase. In addition, calcium did not alter the kinetics of succinate dehydrogenase activation. Calcium and magnesium, in the concentration range of 0.02 to 5 mM, did not influence the NADH dehydrogenase activity of SMP. Energization of SMP by oligomycin addition, however, dramatically influenced the kinetic properties of NADH dehydrogenase. It is proposed that in heart mitochondria, calcium does not affect directly the components of electron transport but it may influence the activity of NADH dehydrogenase indirectly by increasing delta psi.
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PMID:Influence of calcium on NADH and succinate oxidation by rat heart submitochondrial particles. 786 38

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 toxicity of hydrophilic (cholate) and lipophilic (deoxycholate, chenodeoxycholate, and lithocholate) bile acids on the function of the electron transport chain was investigated in intact and disrupted rat liver mitochondria. In intact mitochondria, lipophilic bile acids used at a concentration of 100 mumol/L (0.1 mumol/mg protein) inhibited state 3 and state 3u (dinitrophenol-uncoupled) oxidation rates for L-glutamate, succinate, duroquinol or ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine as substrates. In contrast, state 4 oxidation rates and ADP/oxygen ratios were not significantly affected. At a bile acid concentration of 10 mumol/L (0.01 mumol/mg protein), the state 3 oxidation rate for L-glutamate was decreased in the presence of deoxycholate, chenodeoxycholate or lithocholate, whereas only lithocholate inhibited state 3 oxidation for succinate or duroquinol. In broken mitochondria, inhibition of oxidative metabolism was found for NADH or duroquinol as substrate in the presence of 100 mumol/L lithocholate (0.2 mumol/mg protein) and for duroquinol in the presence of 100 mumol/L chenodeoxycholate. Direct assessment of the activities of the enzyme complexes of the electron transport chain revealed decreased activities of complex I and complex III in the presence of 100 mumol/L deoxycholate or chenodeoxycholate or 10 mumol/L lithocholate. Inhibition of complex IV required higher bile acid concentrations (300 mumol/L for chenodeoxycholate or 30 mumol/L for lithocholate), and complex II was not affected. Both chenodeoxycholate and lithocholate were incorporated into mitochondrial membranes. The phospholipid content of mitochondrial membranes decreased in incubations containing 100 mumol/L (0.1 mumol/mg protein) chenodeoxycholate but was not affected in the presence of 100 mumol/L lithocholate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria. 790 81

The effect of methylglyoxal on the oxygen consumption of Ehrlich-ascites-carcinoma (EAC)-cell mitochondria was tested by using different respiratory substrates, electron donors at different segments of the mitochondrial respiratory chain and site-specific inhibitors to identify the specific respiratory complex which might be involved in the inhibitory effect of methylglyoxal on the oxygen consumption by these cells. The results indicate that methylglyoxal strongly inhibits ADP-stimulated alpha-oxo-glutarate and malate plus pyruvate-dependent respiration, whereas, at a much higher concentration, methylglyoxal fails to inhibit succinate-dependent respiration. Methylglyoxal also fails to inhibit respiration which is initiated by duroquinol, an artificial electron donor. Moreover, methylglyoxal cannot inhibit oxygen consumption when the NNN'N'-tetramethyl-p-phenylenediamine by-pass is used. The inhibitory effect of methylglyoxal is identical on both ADP-stimulated and uncoupler-stimulated respiration. Lactaldehyde, a catabolite of methylglyoxal, can exert a protective effect on the inhibition of EAC-cell mitochondrial respiration by methylglyoxal. We suggest that methylglyoxal possibly inhibits the electron flow through complex I of the EAC-cell mitochondrial respiratory chain.
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PMID:Inhibition of electron flow through complex I of the mitochondrial respiratory chain of Ehrlich ascites carcinoma cells by methylglyoxal. 794 67

In the filarial parasite, Setaria digitata, the mitochondria like particles (MLP) show NAD reduction with sodium lactate. The MLP also reduces dye and ferricyanide with lactate. The ferricyanide reduction by lactate is found to be sensitive to the cytochrome o inhibitor orthohydroxy diphenyl (OHD) and complex I inhibitor rotenone, modulated by ADP (+) and ATP (-) and inhibited by pyruvate and oxaloacetate. MLP shows lactate oxidation sensitive to OHD, rotenone and sodium malonate. Thus, the lactate utilizing complex system, consisting of an NADH generating MLP bound lactate dehydrogenase and a lactate flavocytochrome reductase tightly linked to complex I and cytochrome o, produces ATP in functional association with fumarate reductase complex and other enzyme systems. Hence, this study provides new dimensions to the study of metabolism in filarial parasites.
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PMID:Lactate oxidation coupled to energy production in mitochondria like particles from Setaria digitata, a filarial parasite. 794 57


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