Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nuclear genes (acp-1, ACP1) encoding the mitochondrial acyl carrier protein were disrupted in Neurospora crassa and Saccharomyces cerevisiae. In n. crassa acp-1 is a peripheral subunit of the respiratory NADH : ubiquinone oxidoreductase (complex I). S. cerevisiae lacks complex I and its ACP1 appears to be located in the mitochondrial matrix. The loss of acp-1 in N. crassa causes two biochemical lesions. Firstly, the peripheral part of complex I is not assembled, and the membrane part is not properly assembled. The respiratory ubiquinol : cytochrome c oxidoreductase (complex III) and cytochrome c oxidase (complex IV) are made in normal amounts. Secondly, the lysophospholipid content of mitochondrial membranes is increased four-fold. In S. cerevisiae, the loss of ACP1 leads to a pleiotropic respiratory deficient phenotype.
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PMID:Different respiratory-defective phenotypes of Neurospora crassa and Saccharomyces cerevisiae after inactivation of the gene encoding the mitochondrial acyl carrier protein. 859 52

The amount of control exerted by respiratory chain complexes in isolated nonsynaptic mitochondria prepared from rat brain on the rate of oxygen consumption was assessed using inhibitor titrations. Rotenone, myxothiazol, and KCN were used to titrate the activities of NADH:ubiquinone oxidoreductase (EC 1.6.5.3; complex I), ubiquinol:ferrocytochrome c oxidoreductase (EC 1.10.2.2; complex III), and cytochrome c oxidase (EC 1.9.3.1; complex IV ), respectively. Complexes I, III, and IV shared some of the control of the rate of oxygen consumption in nonsynaptic mitochondria, having flux control coefficients of 0.14, 0.15, and 0.24, respectively. Threshold effects in the control of oxidative phosphorylation were demonstrated for complexes I, III, and IV. It was found that complex I activity could be decreased by approximately 72% before major changes in mitochondrial respiration and ATP synthesis took place. Similarly, complex III and IV activities could be decreased by approximately 70 and 60%, respectively, before major changes in mitochondrial respiration and ATP synthesis occurred. These results indicate that previously observed decreases in respiratory chain complex activities in some neurological disorders need to be reassessed as these decreases might not affect the overall capability of nonsynaptic mitochondria to maintain energy homeostasis unless a certain threshold of decreased complex activity has been reached. Possible implications for synaptic mitochondria and neurodegenerative disorders are also discussed.
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PMID:Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria. 862 18

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

Carnitine is an essential cofactor for long-chain fatty acid oxidation. We characterized the human carnitine transporter in vitro in a cultured skin fibroblast model both at the previously established Km concentration of carnitine uptake in fibroblasts (5 mumol/liter) and at 0.05% Km (0.25 mumol/liter). A rapid exponential dose-dependent decrease in mean percentage of carnitine uptake was demonstrated with increasing concentrations of nigericin, but no significant decrease was found with equimolar amounts of valinomycin. This would suggest that the Na+ gradient is integral to carnitine transport function. Interference of the Na+ (out-in) gradient by nigericin may be secondary to cytoplasmic acidification by this K+ proton ionophore. The rate of uptake was fully saturated at an extracellular Na+ concentration of 150 mmol/liter. Replacement of 150 mmol/liter extracellular Na+ with Li+ resulted in an 80 and a 50% reduction, and replacement with K+ and Rb+ ions resulted in a 100 and an 85 to 90% reduction in carnitine uptake, respectively, at carnitine concentrations of 0.25 and 5 mumol/liter, underlining the specific requirement for the Na+ ion. The effects of different site-specific respiratory chain toxins, namely, rotenone (complex I), antimycin A (complex III), and potassium cyanide (KCN) (complex IV) on carnitine uptake was also examined. A rapid exponential dose-dependent decrease in mean percentage of carnitine uptake with increasing concentrations of inhibitors was demonstrated. These data suggest either a metabolic energy requirement of the carnitine transporter or interference of the Na+ (out-in) gradient by a proton gradient (in-out) secondary to the accumulation of intracellular H+ ions, due to the action of the respiratory chain toxins, further suggesting that the transporter is sensitive to and inhibited by intracellular H+ ions. The effects of several sulfhydryl-binding agents, namely 2,4-dinitrofluorobenzene, N-ethylmaleimide, and mersalyl acid, were examined, and a significant inhibition of carnitine uptake was demonstrated, suggesting that free sulfhydryl groups are also integral to the import function of the human fibroblast transporter.
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PMID:Characterization of the human plasmalemmal carnitine transporter in cultured skin fibroblasts. 863 46

Various authors have suggested that nitric oxide (.NO) exerts cytotoxic effects through the inhibition of cellular respiration. Indeed, in intact cells .NO inhibits glutamate-malate (complex I) as well as succinate (complex II)-supported mitochondrial electron transport, without affecting TMPD/ascorbate (complex IV)-dependent respiration. However, experiments in our lab using isolated rat heart mitochondria indicated that authentic .NO inhibited electron transport mostly by reversible binding to the terminal oxidase, cytochrome a3, having a less significant effect on complex II- and no effect on complex I-electron transport components. The inhibitory action of .NO was more profound at lower oxygen tensions and resulted in differential spectra similar to that observed in dithionite-treated mitochondria. On the other hand, continuous fluxes of .NO plus superoxide (O.(2)(-)), which lead to formation of micromolar steady-state levels of peroxynitrite anion (ONOO-), caused a strong inhibition of complex I- and complex II-dependent mitochondrial oxygen consumption and significantly inhibited the activities of succinate dehydrogenase and ATPase, without affecting complex IV-dependent respiration and cytochrome c oxidase activity. In conclusion, even though nitric oxide can directly cause a transient inhibition of electron transport, the inhibition pattern of mitochondrial respiration observed in the presence of peroxynitrite is the one that closely resembles that found secondary to .NO interactions with intact cells and strongly points to peroxynitrite as the ultimate reactive intermediate accounting for nitric oxide-dependent inactivation of electron transport components and ATPase in living cells and tissues.
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PMID:Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. 864 9

Midazolam, a water soluble benzodiazepine used as a preanaesthetic and hypnotic drug, showed a concentration-related (0.1-0.75 mM) depressant effect on both Adenosine 5'-diphosphate (ADP)-induced oxygen consumption and oxidative phosphorylation of rat liver mitochondria if the substrate was oxidized at different steps in the oxidation chain, but not when the substrate was ascorbate plus tetramethyl-p-phenylenediamine (complex IV). Furthermore, midazolam did not affect citrate synthase activity, but inhibited the 2,4 dinitrophenol (DNP)-uncoupled mitochondrial respiration. This result shows that midazolam primarily acts as a mitochondrial electron transport inhibitor. This inhibition is mainly due to the fact that midazolam decreases NADH ubiquinone reductase (complex I) and ubiquinol cytochrome c reductase (complex III) activities, but it also inhibits complex II activity. Spectrophotometric measurements of redox states of rat skeletal muscle mitochondria cytochromes show a decrease in the reduction of aa3 and c+c1 cytochromes in the presence of the benzodiazepine. Midazolam significantly decreased the reduced ubiquinone/total ubiquinone ratio (evaluated by means of HPLC and electrochemical detection) in rat liver mitochondria in both beta-hydroxybutyrate and succinate. Ubisemiquinone may be the redox component affected by midazolam, whether or not bound to the iron-sulfur proteins present in all three mitochondrial complexes. These effects of midazolam, not necessarily related to the preanaesthetic and hypnotic action are probably mediated via mitochondrial benzodiazepine receptors.
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PMID:Biochemical characterization of the effects of the benzodiazepine, midazolam, on mitochondrial electron transfer. 882 37

Twelve patient cell lines with biochemically proven complex I deficiency were compared for clinical presentation and outcome, together with their sensitivity to galactose and menadione toxicity. Each patient had elevated lactate to pyruvate ratios demonstrable in fibroblast cultures. Each patient also had decreased rotenone-sensitive NADH-cytochrome c reductase (complexes I and III) with normal succinate cytochrome c reductase (complexes II and III) and cytochrome oxidase (complex IV) activity in cultured skin fibroblasts, indicating a deficient NADH-coenzyme Q reductase (complex I) activity. The patients fell into five categories: severe neonatal lactic acidosis; Leigh disease; cardiomyopathy and cataracts; hepatopathy and tubulopathy; and mild symptoms with lactic acidaemia. Cell lines from 4 out of the 12 patients were susceptible to both galactose and menadione toxicity and 3 of these also displayed low levels of ATP synthesis in digitonin-permeabilized skin fibroblasts from a number of substrates. This study highlights the heterogeneity of complex I deficiency at the clinical and biochemical level.
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PMID:NADH-coenzyme Q reductase (complex I) deficiency: heterogeneity in phenotype and biochemical findings. 889 26

Lymphoblastoid cells are useful materials for the diagnosis and basic studies of many human genetic disorders. To elucidate the etiology of Leigh syndrome, biochemical analyses and mitochondrial DNA analyses were performed on cultured lymphoblastoid cells from 20 patients with the clinical characteristics of this disorder. In 9 of 20 cases, we were able to define the following defects. Eight patients had biochemical defects, including 3 with pyruvate dehydrogenase complex (PDHC), 3 with cytochrome c oxidase (complex IV), and 2 with NADH-cytochrome c reductase (complex I) deficiencies. Two of 3 patients with PDHC deficiency were diagnosed with thiamine-responsive PDHC deficiency. One patient had a point mutation (T-->G) of mitochondrial DNA at nucleotide position 8993. These results indicate that the underlying defects in Leigh syndrome are heterogeneous and cultured lymphoblastoid cells are very useful materials for diagnosis of the etiology of Leigh syndrome.
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PMID:[Defects of pyruvate metabolism in cultured lymphoblastoid cells of 20 patients with Leigh syndrome]. 894 Aug 76

For years, it has been known that neuroleptics have the capacity to interfere with the mitochondrial respiratory chain in vitro. We report that haloperidol and fluphenazine, classical neuroleptics, cause a generalized reduction in the activity of NADH: ubiquinone oxidoreductase (complex I) in the rat brain in vivo, an effect that was not observed with the atypical neuroleptic, clozapine. MPTP, which bears significant structural similarities with haloperidol, also demonstrated a significant reduction in complex I activity after low-dose, chronic administration. Interestingly, an increase in the activity of cytochrome-c oxidase (complex IV), probably reflecting enhanced functional neuronal activity, was observed in the frontal cortex of all chronically treated animals, an effect that is unlikely to result from compensation for the inhibition of complex I. Results suggest that previous findings, in which a reduction in the activity of cytochrome-c oxidase was observed in postmortem brain samples from schizophrenics, are not dependent on treatment with neuroleptics.
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PMID:Neuroleptic-induced mitochondrial enzyme alterations in the rat brain. 899 5

The legume Vicia sativa (common vetch) harbors the neurotoxic nonprotein amino acid beta-cyano-L-alanine (BCLA) and its gamma-glutamyl derivative. BCLA elicits hyperexcitability, convulsions, and rigidity in chicks and rats after oral or intraperitoneal administration, but the mechanism of its action is unknown. The effect of different concentrations of BCLA (0.075-10.0 mM) has been investigated in an organotypic tissue culture system. BCLA concentrations of 0.075 and 0.60 mM had no effect, even up to 6 hr. No changes were observed in cultures treated with 1 mM BCLA for 4 hr. BCLA (2.0-10.0 mM) induces concentration-dependent changes in the explants. The explants display neurona vacuolation, chromatin, clumping, and dense shrunken cells, a pathological response generally seen with excitotoxin. MK-801 (35 microM), which blocks the open ion channel associated with the N-methyl-D-aspartate (NMDA) class of glutamate receptors, attenuates the neurotoxic property of BCLA, while the non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (10-20 microM), provides no significant protection. Treatment of isolated mouse brain mitochondria with up to 5 mM BCLA had no inhibitory effect on the activity of NADH dehydrogenase (complex I) or cytochrome or oxidase (complex IV), a cyanide-sensitive enzyme. These results suggest that the neurotoxicity of BCLA (or derivative) is mediated directly or indirectly through NMDA receptors.
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PMID:beta-Cyano-L-alanine toxicity: evidence for the involvement of an excitotoxic mechanism. 902 49


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