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)

Continuous exposure of Chinese hamster ovary (CHO) cells to an atmosphere of 98% O2, 2% CO2 (normobaric hyperoxia) leads within a period of several days to cytostasis and clonogenic cell death. Here we report respiratory failure as an important early symptom of oxygen intoxication in CHO cells, resulting in a more than 80% inhibition of oxygen consumption within 3 days of hyperoxic exposure. This inhibition appeared to be correlated with selective inactivation of three mitochondrial key enzymes, NADH dehydrogenase, succinate dehydrogenase, and alpha-ketoglutarate dehydrogenase. The latter enzyme controls the influx of glutamate into the Krebs cycle and is particularly critical for oxidative ATP generation in most cultured cells, which depends on exogenous glutamine rather than glucose as a carbon source. As expected, the inactivation of alpha-ketoglutarate dehydrogenase was correlated with a fall in cellular glutamine utilization, which became apparent from the first day of hyperoxic exposure. Thereafter, glucose utilization and lactate excretion started to increase, up to 3-fold, indicating a cellular response to respiratory failure aimed at increased ATP generation from glycolysis. However, in spite of this response, the cellular ATP level progressively decreased, up to 2.5-fold. Thus, killing of CHO cells by normobaric hyperoxia seems to be due to a severe disturbance of mitochondrial metabolism eventually leading to a depletion of cellular ATP pools.
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PMID:Respiratory failure and stimulation of glycolysis in Chinese hamster ovary cells exposed to normobaric hyperoxia. 235 58

m-Iodobenzylguanidine (MIBG) is a functional analogue of the neurotransmitter norepinephrine. Radio-iodinated 131I-MIBG is used clinically as a tumor-targeted radiopharmaceutical agent in the diagnosis and treatment of adrenergic tumors. Native MIBG has previously been demonstrated to be cytotoxic in cultured cells and to produce anti-tumor responses in animals when non-toxic schedules are used. In this study the effect of MIBG was investigated on isolated rat liver mitochondria and on various tumor cell lines (human neuroblastoma SK-N-SH, mouse neuroblastoma N1E115 and mouse lymphosarcoma S49). Results revealed that MIBG inhibits respiration of isolated liver mitochondria at complex I of the respiratory chain, without affecting F1 ATP-ase. In cell lines, impairment of the mitochondrial respiration was evident from reduced oxygen consumption and decreased intracellular ATP levels. In response to this effect, the glycolytic flux was stimulated as shown by increased glucose consumption and lactic acid production. Cytotoxicity of MIBG was proportional to drug-induced alterations in glucose metabolism.
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PMID:Impaired mitochondrial respiration and stimulated glycolysis by m-iodobenzylguanidine (MIBG). 238 75

The main target of local anaesthetics on nervous tissue is the sodium channel. Molecular biology and electrophysiology have shown different mechanisms of action on this sodium channel, which depend on the chemical structure and electrostatic charge of the local anaesthetic molecule. There are two main types of action, shown up on the isolated axon, a direct one on the sodium channel itself and an alteration in the lipids surrounding the channel. These effects have been shown on the isolated axon and explain the anaesthetic effect by an inhibition of the sodium current. Experimental studies have also shown the effects of local anaesthetics on different organelles within the cell, and so on intracellular metabolism. Mitochondrial energetic metabolism, and therefore ATP synthesis, is reduced by local anaesthetics at several levels. The respiratory enzyme chain is inhibited by small concentrations of local anaesthetic, especially NADH dehydrogenase and ubiquinone succinate dehydrogenase. Moreover, local anaesthetics increase the mitochondrial membrane permeability to protons, thus removing the moving force behind ATPase activity in ATP synthesis; this leads to a drastic fall in available energy. This effect is further increased by a direct inhibition of ATPase and ATP/ADP translocation. Other enzyme systems of other organelles are also disturbed by local anaesthetics, such as the endoplasmic reticular Ca++ ATPase, which is inhibited, so altering the calcium concentration within the cytosol. Local anaesthetics also inhibit lipolysis and glycogenesis. Receptors such as the acetylcholine receptors are blocked by local anaesthetics. The mechanism of action of these drugs on all these protein systems is two-fold: an alteration of protein structure, but also of the lipids surrounding them.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Molecular mechanism of action of local anesthetics]. 245 46

An artificial proton gradient provided sufficient energy to drive reverse electron transport from succinate to NADH:ubiquinone oxidoreductase in chromatophores isolated from Rhodospirillum rubrum. The pH gradient created was able to reduce NAD+. In chromatophores, the optimal rate of NAD+ reduction was about 0.4-0.45 mumol NADH formed/min.mumol bacteriochlorophyll at delta pH 3. The presence of oligomycin was an obligate factor in the assay in order to observe the maximal rate of NAD+ reduction. The rate of NADH formation was dependent on the size of the induced pH gradient. The total NADH formed had a threshold value for the imposed delta pH. The effect of different inhibitors and uncouplers was demonstrated. Comparison between ATP, PPi, and light with the pH jump driven NAD+ reduction rate was studied.
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PMID:delta pH driven energy-linked NAD+ reduction in Rhodospirillum rubrum chromatophores. 250 79

We report the nucleotidic mapping of a 4,666 base pairs deletion of the human mitochondrial DNA localized at positions 8571 and 13237 in a Kearns-Sayre syndrome patient. The gene fusion between the 15 N terminal amino acid residues of ATP synthetase subunit 6 and the 303 C terminal aminoacids of NADH dehydrogenase yields a potential protein of 35,000 d MW called A6-ND5. Deletion boundaries show a short inverted repeat ATCXTA. The heteroplasmic deletion mechanism is discussed in view of these data.
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PMID:[Nucleotide mapping and a kinetic model of a heteroplasmic deletion of 4,666 base pairs from mitochondrial DNA in the Kearns-Sayre syndrome]. 251 65

Rotenone-sensitive NADH dehydrogenase activity and Lubrol stimulation of cytochrome oxidase activity were measured to assess the opposite membrane polarity of beef heart mitoplast and inside-out particle preparations. The ATP-Pi exchange activity of mitoplasts was not affected by their incubation at pH 8.9 in the presence of 5 mM EDTA (a treatment known to extract coupling factor B (F beta) from submitochondrial particles), nor was it stimulated by the addition of F beta to intact and alkaline treated mitoplast preparations. In contrast, the exchange activity of inside-out particles was decreased 18 fold by the alkaline/EDTA treatment and was almost completely restored by the addition of F beta to F beta-depleted particles. From these results it is concluded that in beef heart mitochondria, the coupling factor F beta is bound to the matrix-side of the inner mitochondrial membrane.
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PMID:Evidence that coupling factor B is bound to the matrix side of the inner mitochondrial membrane. 256 42

The influence of hyperthermia on liver mitochondrial respiration and liver metabolites levels was studied by increasing body temperature to 41.0 degrees C in rats under oxygen and nitrous oxide anesthesia maintaining constant PaCo2. At 41.0 degrees C, the increase in ATP and energy charge level (EC) by Atkinson and the increase of state 3 and RCR in NADH linked substrate were observed. After maintaining body temperature at 41.0 degrees C for 30 minutes, the decrease in ATP, EC, state 3, RCR and ADP/O were observed. The degree of change from 38.0 degrees C to 41.0 degrees C in state 3, state 4, RCR and ADP/O was greater in NADH linked substrate than in non-NADH one. After keeping body temperature at 38.0 degrees C for 30 minutes by the whole body cooling, the recovery of EC, state 3 and RCR was observed. The effects of cooling with drugs (dantrolen or methyl-prednisolone) had no consistent effect. These findings suggest that the hyperthermic stress on mitochondrial respiration is focused on complex I in electron transport system.
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PMID:[Liver mitochondrial respiration during hyperthermia]. 257 74

The in vivo action of cyclosporine A (CS) on rat renal cortical mitochondria was investigated. CS (30 mg.kg-1.day-1) given orally to rats for 30 days caused an augmentation of renal mitochondrial oxidative phosphorylation. The ADP-stimulated respiratory rate was increased by 37.0% with glutamate plus malate as respiratory substrates (P less than 0.025) but not with succinate-supported respiration, indicating enhancement of mitochondrial complex I activity. This reaction may be a response to the 32.5% reduction of renal blood (P less than 0.005) in the CS-treated group, possibly serving to maximize ATP synthesis during ischemia. Ligation-induced decreases in renal blood flow also resulted in enhancement of mitochondrial complex I activity.
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PMID:Cyclosporine augments renal mitochondrial function in vivo and reduces renal blood flow. 258 85

The inhibition of NADH dehydrogenase by 1-methyl-4-phenylpyridinium (MPP+) leading to ATP depletion has been proposed to explain cell death in the expression of the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Electron paramagnetic resonance studies show no effect of MPP+ on the reduction of the iron-sulfur clusters of NADH dehydrogenase. Mitochondria inhibited by MPP+ were sonicated and both the NADH oxidase and the NADH-Q reductase activities were measured. NADH oxidase activity was not fully restored to control levels, but NADH-Q reductase activity was the same as that of the control. Neither succinate-oxidase nor succinate-Q reductase activities were inhibited. These data indicate that MPP+ interaction with NADH dehydrogenase interferes with the passage of electrons from the iron-sulfur cluster of highest potential to endogenous Q10 but that the inhibition can be relieved by the addition of a small, water-soluble Q analog. Inhibition at this site is sufficient to explain the inhibition of respiration and no inhibition of other mitochondrial functions was observed.
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PMID:The inhibition site of MPP+, the neurotoxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is near the Q-binding site of NADH dehydrogenase. 282 83

Electron transfer activities and steady state reduction levels of Fe-S centers of NADH-Q oxidoreductase were measured in mitochondria, submitochondrial particles (ETPH), and complex I after treatment with various reagents. p-Chloromercuribenzenesulfonate destroyed the signal from center N-4 (gx = 1.88) in ETPH but not in mitochondria, showing that N-4 is accessible only from the matrix side of the inner membrane. N-Bromosuccinimide also destroyed the signal from N-4 but without inhibiting rotenone-sensitive electron transfer to quinone, suggesting a branched pathway for electron transfer. Diethylpyrocarbonate caused oxidation of N-3 and N-4 in the steady state without changing N-1, suggesting N-1 is before N-3 and N-4. Difluorodinitrobenzene and dicyclohexylcarbodiimide inhibited oxidation of all Fe-S centers and tetranitromethane inhibited reduction of all Fe-S centers. Titrations of the rate of superoxide (O2-) generation in rotenone-treated submitochondrial particles were similar with the ratio [NADH]/[NAD] and that of 3-acetyl pyridine adenine nucleotide in spite of different midpoint potentials of the two couples. On reaction with inhibitors the inhibition of O2- formation was similar to that of ferricyanide reductase rather than quinone reductase. The rate of O2- formation during ATP-driven reverse electron transfer was 16% of the rate observed with NADH. The presence of NAD increased the rate to 83%. The results suggest that bound, reduced nucleotide, probably E-NAD., is the main source of O2- in NADH dehydrogenase. The effect of ATP on the reduction levels of Fe-S centers in well-coupled ETPH was measured by equilibrating with either NADH/NAD or succinate/fumarate redox couples. With NADH/NAD none of the Fe-S centers showed ATP induced changes, but with succinate/fumarate all centers showed ATP-driven reduction with or without NAD present. The effect on N-2 was smaller than that on N-1, N-3, and N-4. These observations indicate that the major coupling interaction is between N-2 and the low potential centers, N-1, N-3, and N-4. Possible schemes of coupling in this segment are discussed.
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PMID:Studies on the electron transfer pathway, topography of iron-sulfur centers, and site of coupling in NADH-Q oxidoreductase. 284 70


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