Thorium inhibits human respiratory chain complex IV (cytochrome c oxidase)
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Abstract: Carbon monoxide (CO) toxicity is the result of a combination of tissue hypoxia and direct CO‐mediated damage at a cellular level, since not all the signs and symptoms presented can be explained only by the formation of carboxyhaemoglobin. Mitochondria, specially the electron transport chain, seem to be the target for CO at a subcellular level. However, the direct effect of CO in individual complexes of the human mitochondrial respiratory chain has not been completely elucidated. We here studied the in vitro effect of CO on individual complexes of the mitochondrial respiratory chain of human mitochondria. We obtained muscle tissue from 10 healthy people who underwent orthopaedic surgery for hip replacement. Isolated mitochondria were incubated for 5 min. under CO concentrations of 50, 100 and 500 ppm. Afterwards, enzymatic activities of individual complexes of the mitochondrial respiratory chain were assessed in vitro and compared with those obtained in basal (synthetic air without CO) conditions. Cytochrome c oxidase (complex IV of the mitochondrial respiratory chain) activity showed a decrease from 836±439 nmol/min./mg of mitochondrial protein after air incubation to 670±401, 483±182, and 379±131 nmol/min./mg after 50, 100 and 500 ppm of CO incubation, respectively (20%, 42% and 55% decrease in cytochrome c oxidase activity). This gradual decrease in cytochrome c oxidase was found to be statistically significant (P<0.001). Other complex activities showed no any significant variation. Carbon monoxide is toxic for mitochondria in man, altering the mitochondrial respiratory chain at the cytochrome c oxidase level. This inhibition in cytochrome c oxidase may play a role in the development of the symptoms observed in acute CO poisoning, and in some diseases related to smoking.
Mitochondrial respiratory chain
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Beef heart cytochrome oxidase (EC 1.9.3.1) prepared in this laboratory consistently presents 10 Coomassie blue staining zones on SDS–polyacrylamide gel electrophoresis. At pH 7.0 only two of these polypeptides (III and VIa) are labelled by radioactive N-ethyl maleimide (NEM). The labelling of VIa is variable and correlates with the activity of particular oxidase preparations. When cytochrome oxidase is isolated from alkylated membranes, either mitochondria or electron transport particles, polypeptide VIa is found not to be labelled; polypeptide III is more strongly labelled than when isolated oxidase is alkylated, and label now appears in polypeptide I which is not alkylated upon treatment of isolated oxidase with NEM.
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Cytochrome oxidase was purified from bovine-heart mitochondria and its enzymatic properties were examined. The purified cytochrome oxidase was identified by its absorption spectrum and chromatogram through gel filtration. The specific activity, purification degree and yield of purified cytochrome oxidase were 18 nmol/mg/ml/min, 24.83 fold and 0.93%, respectively. The activity of the enzyme assayed by a ferrocytochrome system was optimized at and pH 6.5. Examining the effect of nonionic detergents established that cytochrome oxidase was deactivated by Triton X-100. The oxidase was activated by Tween 80 and deactivated by Tween 20. The Michaelis constant and maximum velocity of the oxidase for ferrocytochrome c were 0.032~0.044 mM and 0.019~0.021 mM/min, respectively. After adaption to basal diet for a week, experimental diets containing 6 mg Cu/kg, or zero mg Cu/kg, or 12 mg Cu/kg were fed to a control group, a copper-free group and a copper-rich group of Sprague-Dawley rats, respectively, for 4 weeks. The specific activities assayed for the ferrocytochrome system of isolated cytochrome oxidase from the rat liver of control, copper-free, and copper-rich group were 1.00, 1.19, and 0.878 nmol/mg/ml/min, respectively. Their degrees of purification were 11.38, 10.82 and 8.78 fold, respectively. The specific activities for liver and heart mitochondrial cytochrome oxidase of copper-free/copper-rich groups assayed using the ferrocytochrome system were 81.4% and 96.4%/64.1% and 61.1%, respectively, compared with those of the control.
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Cytochrome c oxidase is the last respiratory complex of the electron transfer chain in mitochondria and is responsible for transferring electrons to oxygen, the final acceptor, in the classical respiratory pathway. The essentiality of this step makes it that depletion in complex IV leads to lethality, thereby impeding studies on complex IV assembly and respiration plasticity in plants. Here, we characterized Arabidopsis (Arabidopsis thaliana) embryo-lethal mutant lines impaired in the expression of the CYTOCHROME C OXIDASE DEFICIENT1 (COD1) gene, which encodes a mitochondria-localized PentatricoPeptide Repeat protein. Although unable to germinate under usual conditions, cod1 homozygous embryos could be rescued from immature seeds and developed in vitro into slow-growing bush-like plantlets devoid of a root system. cod1 mutants were defective in C-to-U editing events in cytochrome oxidase subunit2 and NADH dehydrogenase subunit4 transcripts, encoding subunits of respiratory complex IV and I, respectively, and consequently lacked cytochrome c oxidase activity. We further show that respiratory oxygen consumption by cod1 plantlets is exclusively associated with alternative oxidase activity and that alternative NADH dehydrogenases are also up-regulated in these plants. The metabolomics pattern of cod1 mutants was also deeply altered, suggesting that alternative metabolic pathways compensated for the probable resulting restriction in NADH oxidation. Being the first complex IV-deficient mutants described in higher plants, cod1 lines should be instrumental to future studies on respiration homeostasis.
Alternative oxidase
Mitochondrial respiratory chain
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