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)

A female infant was seen at the age of 2 months because of hypotonia, delayed motor development, and lactic acidosis, and she died at age 13 months due to respiratory failure. In a muscle specimen taken at 11 months and in a liver specimen obtained 1.5 hours postmortem, we found decreased activities of cytochrome c oxidase and long-chain acyl coenzyme A dehydrogenase. Neuropathological changes were typical for Leigh's subacute necrotizing encephalomyelopathy. To our knowledge, this is the first report of a combined defect of complex IV of the respiratory chain and of the long-chain specific acyl coenzyme A dehydrogenase of beta-oxidation in muscle and liver.
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PMID:Cytochrome c oxidase deficiency and long-chain acyl coenzyme A dehydrogenase deficiency with Leigh's subacute necrotizing encephalomyelopathy. 131 9

A histochemical analysis of mitochondrial enzyme activity was carried out in 103 human diaphragmatic skeletal muscles from 49 subjects of different ages, obtained either at the time of abdominal surgery or at necropsy. Evidence of respiratory failure (cytochrome oxidase negativity) was seen in occasional fibres from the fourth decade on with an approximate 10-fold increase between the fourth and ninth decade (0.16% to 2.85%). A similar incidence of mitochondrial failure in CNS neurones to that documented in skeletal muscle could easily account for attrition of 25% of neurones over a 50-year period as reported in the literature. Possible theoretical relationships between morphological markers of mitochondrial failure and cell attrition are explored. While the projections from muscle to neurone are somewhat speculative, it is clear that if a similar extent of mitochondrial pathology exists in the brain to that documented in skeletal muscle, this could easily account for neuronal loss in the ageing brain.
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PMID:Respiratory chain failure in adult muscle fibres: relationship with ageing and possible implications for the neuronal pool. 138 55

The use of amyl nitrite and phenoxybenzamine in the treatment of acute cyanide poisoning was evaluated. Sixty anesthetized beagle dogs were injected i.v. with sodium cyanide (2.5 mg/kg) and were followed for changes in the heart rate, electrocardiogram, respiration, blood pressure and methemoglobin concentration. Twenty control dogs died within 5 to 7 min, showing severe bradycardia, a sharp drop in arterial blood pressure, and respiratory paralysis. Pretreatment with phenoxybenzamine (0.5 mg/kg) prevented these changes in 8 of 10 dogs; however, this drug was ineffective if given after the cyanide. In contrast, amyl nitrite given after cyanide administration reversed both the cardiovascular changes and the respiratory paralysis in 24 of the 30 dogs studied. These changes occurred before the formation of significant amounts of methemoglobin and indicate that early death caused by cyanide may be due in part to cardiovascular-respiratory failure in addition to the classic poisoning of the cytochrome oxidase system. These studies indicate that phenoxybenzamine prevents and amyl nitrite reverses the otherwise lethal effects of cyanide.
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PMID:Studies of cyanide poisoning. 286 Aug 82

A 3-day-old girl had a syndrome of lethargy and lactic acidosis. Pregnancy and delivery had been normal; there was no consanguinity or family history of neuromuscular disease. At age 4 1/2 months, she had generalized weakness, hypotonia, areflexia, and macroglossia. She developed cyanosis and respiratory failure, and marked cardiomegaly was noted. She died at age 8 1/2 months of cardiac arrest. Results from a muscle biopsy specimen obtained at age 4 1/2 months showed ragged-red fibers and increased glycogen and lipid droplets. With the cytochrome c oxidase reaction, only 5% of the fibers stained positively in the biopsy specimen. Cytochrome c oxidase activity was 7.3% of normal in muscle mitochondria and 12.2% of normal in heart mitochondria. Reduced-minus-oxidized cytochrome spectra showed lack of the cytochrome aa3 peak. Immunotitration using antibodies against purified human heart cytochrome c oxidase showed normal amount of cross-reacting material in both heart and muscle. The genetic error could have involved a cytochrome c oxidase isozyme common to heart and muscle.
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PMID:Myopathy and fatal cardiopathy due to cytochrome c oxidase deficiency. 302 95

Measurement of pyruvate and lactate produced from glucose by confluent skin fibroblast cultures from 95 patients with lactic acidemia revealed 10 in whom the lactate/pyruvate ratio (L/P) was increased (L/P = 57 to 232) compared with that observed in control cell lines (L/P = 18 to 35). Mitochondria prepared from these cells revealed two types of respiratory chain defect. In four patients the deficient activity was present in NADH-coenzyme Q reductase (14% to 21% of controls), and in six the deficiency was in cytochrome c oxidase (21% to 28% of controls). The four patients with NADH-coQ reductase deficiency presented early with lactic acidosis, respiratory failure, anorexia, and hypotonia; all four died within 7 months. The group with cytochrome oxidase deficiency had a somewhat later (18 months to 2 years of age) presentation with milder lactic acidemia, but also with hypotonia and anorexia. They had delayed development, beginning to walk and talk at 18 to 24 months, and then slowly regressed. Although an investigation of central nervous system disorders in this latter group has not been possible, the clinical progression fits into the broad category of Leigh disease. We conclude that in these two groups respiratory chain defects can be detected and localized by the use of skin fibroblast cultures.
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PMID:Clinical presentation of mitochondrial respiratory chain defects in NADH-coenzyme Q reductase and cytochrome oxidase: clues to pathogenesis of Leigh disease. 302 93

Subacute necrotizing encephalomyelopathy (Leigh's syndrome) is a rare neurodegenerative disease in the adult. The precise metabolic defect is unknown, but abnormalities of a mitochondrial enzyme system related to cytochrome-c oxidase or pyruvate dehydrogenase are described. The clinical picture usually consists of an altered breathing pattern, oculomotor paralysis, other signs of cranial nerve dysfunction, ataxia, myoclonic jerks, nystagmus, generalized seizures, optic atrophy and demyelinating peripheral neuropathy. Hypopnea leads to CO2-retention with consecutive loss of consciousness demanding mechanical ventilation. Respiratory failure is the most frequent cause of death. Here we describe two patients with adult onset Leigh's syndrome and we discuss the longterm treatment strategies including vitamin B1 and CPAP mask.
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PMID:[Adult Leigh syndrome. A rare differential diagnosis of central respiratory insufficiency]. 771 56

We report on a boy who developed proximal renal tubular acidosis with loss of carnitine at the age of about 6 months. A few months later he began to suffer from progressive muscular weakness and neurological disturbances. Blood biochemistry showed elevated lactate and beta-hydroxybutyrate with increased lactate/pyruvate and beta-hydroxybutyrate/acetoacetate ratios. A high urinary excretion of lactate and citric acid cycle intermediates was found. These results indicated a defect of the mitochondrial respiratory chain. Analysis of biopsy material from skeletal muscle revealed low activities of all respiratory chain complexes. In muscle and fibroblasts cytochrome c-oxidase (complex IV) was absent. Despite high dose multi-vitamin therapy the boy died at the age of 30 months from central respiratory failure. At autopsy the neuropathological diagnosis of Leigh disease was made.
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PMID:Absence of cytochrome c oxidase activity in a boy with dysfunction of renal tubules, brain and muscle. 819 61

Mitochondrial respiratory failure secondary to complex I inhibition may contribute to the neurodegenerative process underlying nigral cell death in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be inhibitors of complex I, and have been implicated in the cause of PD as endogenous neurotoxins. To determine the potency and structural requirements of isoquinoline derivatives to inhibit mitochondrial function, we examined the effects of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (11 isoquinolines, 2 dihydroisoquinolines, and 9 1,2,3,4-tetrahydroisoquinolines) and MPP+ on the enzymes of the respiratory chain in mitochondrial fragments from rat forebrain. With the exception of norsalsolinol and N,n-propylisoquinolinium, all compounds inhibited complex I in a time-independent, but concentration-dependent manner, with IC50s ranging from 0.36-22 mM. Several isoquinoline derivatives were more potent inhibitors of complex I than 1-methyl-4-phenylpyridinium ion (MPP+) (IC50 = 4.1 mM), the most active being N-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.36 mM) and 6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.38 mM). 1,2,3,4-Tetrahydroisoquinoline was the least potent complex I inhibitor (IC50 approximately 22 mM). At 10 mM, only isoquinoline (23.1%), 6,7-dimethoxyisoquinoline (89.6%), and N-methylsalsolinol (34.8%) inhibited (P < 0.05) complex II-III, but none of the isoquinoline derivatives inhibited complex IV. There were no clear structure-activity relationships among the three classes of isoquinoline derivatives studied, but lipophilicity appears to be important for complex I inhibition. The effects of isoquinoline derivatives on mitochondrial function are similar to those of MPTP/MPP+, so respiratory inhibition may underlie their reported neurotoxicity.
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PMID:Inhibition of complex I by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 861 71

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

Several recent studies have suggested that skeletal muscle bioenergetics are abnormal in patients with chronic obstructive pulmonary disease (COPD). This study investigates the activity of cytochrome oxidase (COX), the terminal enzyme in the mitochondrial electron transport chain, and the expression of two mitochondrial DNA genes related to COX (mRNA of subunit I of COX [COX-I] and the RNA component of the 12S ribosomal subunit [12S rRNA]), in quadriceps femoris muscle biopsies obtained from COPD patients with various degrees of arterial hypoxemia, and from healthy sedentary control subjects of similar age. The activity of COX was measured spectrophotometrically in fresh tissue at 37 degrees C with excess substrate. RNA transcripts were measured using reverse transcription and polymerase chain reaction. The measurements of mRNA COX-I and 12S rRNA were normalized to the mRNA of actin, which is a housekeeping gene not influenced by hypoxia. We found that, compared with control subjects, COPD patients with chronic respiratory failure (PaO2 < 60 mm Hg) showed increased COX activity (p < 0.05). Further, the activity of COX was inversely related to arterial PO2 value (Rho -0.59, p < 0.01). The COX-I mRNA content was not different between patients and control subjects but patients with chronic respiratory failure had higher levels of 12S rRNA (p < 0.05), which were again inversely related to PaO2 (Rho -0.49, p < 0.05). These results indicate that the activity of COX is increased in skeletal muscle of patients with COPD and chronic respiratory failure, and they suggest that this is likely regulated at the translational level by increasing the number of mitochondrial ribosomes.
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PMID:Cytochrome oxidase activity and mitochondrial gene expression in skeletal muscle of patients with chronic obstructive pulmonary disease. 960 16


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