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:1.9.3.1 (cytochrome oxidase)
8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inorganic lead, added to the diet of suckling rat in high doses, produces an encephalopathy similar to that seen in the immature human. Pathologic changes of edema and hemorrhage are seen earliest and are most prominent in the cerebellum. In this study, we measured respiration in cerebral hemisphere and cerebellar mitochondria isolated from led-fed and age-matched normal rat pups. Lactating mothers were begun on ad libitum feedins containing 4% lead carbonate when their pups were 2 weeks old. Mitochondria were isolated by differential centrifugation. Oxygen consumption was measured polarographically, NAD-linked respiration was measured with oxidation of the substrate pair, glutamate and malate. Cytochrome oxidase (cytochrome c oxidase, EC. 1.9.3.1) activity was measured in the presence of tetramethyl-p-phenylenediamine dihydrochloride (TMPD) and ascorbate. Within 2 days of starting lead feedings, rat pups showed a significant loss in body weight (P less than 0.02) and, after 1 week, a significant loss in cerebral hemisphere wet weight (P less than 0.01) compared with controls. Overt encephalopathy appeared in pups from two of nine litters receiving lead feedings for 1 week and in half of the litters after 2 weeks of feedings. None of the lead-fed mothers developed encephalopathic signs. With oxidation of the NAD-linked substrate pair, there was a progressive decrease, relative to controls, in ADP/O ratios in both cerebellar and cerebral mitochondria from lead-fed animals. After 2 weeks these differences were significant in mitochondria from both regions (cerebellum, P less than 0.02; cerebrum, P less than 0.005). Respiratory control ratios were significantly lower in cerebellar mitochondria from lead-fed rats within 2 days of beginning feedings (P less than 0.02) and in mitochondria from both regions after 2 weeks of lead feedings (cerebellum, P less than 0.01; cerebrum, P less than 0.05). The decrease in control ratios in cerebellar mitochondria from animals receivint lead feedings for 1 week or less was due to a small decrease in state 3 respiration and a large, but inconsistent, increase in state 4 respiration. The decrease in control ratios in both cerebellar and cerebral hemisphere mitochondria after 2 weeks of lead feedings was due to a marked inhibition of state 3 respiration, relative to controls (cerebellum, P less than 0.01; cerebral hemisphers, P less than 0.05). In cerebellar mitochondria from lead-fed animals, cytochrome oxidase activity showed similar changes compared with controls: a highly significant (P less than 0.001) increase within 2 days of beginning feedings and a significant (P less than 0.01) decrease after 2 weeks of feedings.
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PMID:Early effects of inorganic lead on immature rat brain mitochondrial respiration. 17 53

Using in situ hybridization and histochemistry we have studied muscle biopsy samples from eight patients with mitochondrial encephalomyopathies and known defects of mitochondrial DNA (mtDNA). In four patients with heteroplasmic mtDNA deletions there were focal accumulations of deleted mtDNA and its transcripts within ragged red fibres (RRF). In one of these, a probe designed specifically to detect deleted mtDNA identified abundant deleted mtDNA and its fusion transcript in RRF and lesser accumulations in non-ragged red cytochrome oxidase (COX) deficient fibres. A further patient with a deletion involving the heavy strand promoter region showed accumulation of deleted mtDNA and light strand transcripts in RRF, but concomitant depletion of all heavy strand transcripts. In all patients with deletions, normal mtDNA transcripts were depleted in COX deficient fibres irrespective of ragged red change. Deleted mtDNA was rare or absent in normal fibres. Within RRF, COX activity was more profoundly impaired in patients with deletions involving COX subunits. In two patients heteroplasmic for the base pair (bp) 3243 mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS), RRF contained a great excess of mtDNA and transcripts of all species. Some RRF showed excess COX activity. Non-ragged red COX deficient fibres showed equal increases of ribosomal RNA (rRNA) and messenger RNA, suggesting that focal biochemical defects were not associated with a quantitative defect of transcription termination at the 3' end of the 16S rRNA which might be predicted. A patient heteroplasmic for the bp 8344 mutation (associated with myoclonic epilepsy and ragged red fibres: MERRF) showed subnormal COX activity within RRF, although the tissue distribution of mtDNA and its transcripts was similar to that seen with the bp 3243 mutation. Within mitochondrial encephalomyopathies, the relationships between the distribution and expression of abnormal mtDNA and the focal biochemical consequences are complex and heterogeneous.
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PMID:A molecular genetic study of focal histochemical defects in mitochondrial encephalomyopathies. 160 73

During a 4-year period 1984 to 1988, 20 children referred with manifestations of central nervous system or neuromuscular disease combined with hyperlactatemia were found to have a mitochondrial disease. Each diagnosis was based on the results of thorough biochemical and morphologic investigations. The patients were separated into one series with mainly encephalopathy (n = 14) and another with mainly myopathy (n = 6). The patients with encephalopathy had the following syndromes: Kearns-Sayre (n = 2), MERRF (myoclonus epilepsy and ragged red fibers; n = 2), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes; n = 3), Alpers (n = 3), Leigh (n = 1), and other variants (n = 3). In patients with myopathy, three had hypertrophic nonobstructive cardiomyopathy. Ultrastructural abnormalities of mitochondria were the most common morphologic changes in the muscle biopsies. Complex I deficiency was most common in the patients with encephalopathy. All of the patients with myopathy had complex IV deficiency. Mutations of mitochondrial DNA were found in six patients with encephalopathy. We conclude that identification of defects at the DNA level and determination of the phenotypic expression with clinical, morphologic, and biochemical methods are fundamental for future rational classification of mitochondrial disorders.
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PMID:Mitochondrial encephalomyopathies in childhood. II. Clinical manifestations and syndromes. 186 Dec 10

Cultured skin fibroblasts from patients with lacticacidemia were incubated with glucose for 1 h and the lactate and pyruvate production measured. Those patients with increased lactate to pyruvate ratios were further analyzed for the cause of the abnormal redox state. Two categories of patients are described. The first contains patients with either severe or partial cytochrome oxidase deficiency; this group can be broken down further into patients with Leigh's disease, Kearns-Sayre syndrome, and liver-specific cytochrome oxidase deficiency. In this group, the rise in lactate to pyruvate ratio roughly correlated with the severity of the defect. The second patient category had defects located in complex I of the mitochondrial respiratory chain. This is easily demonstrated in the most severely affected patients with the fatal infantile form of the disease. Patients with severe defects in either complex I or cytochrome oxidase had complexes that were only partially assembled. Patients with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes demonstrated only minor changes in redox state and in the behavior of the mitochondrial respiratory chain.
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PMID:The use of skin fibroblast cultures in the detection of respiratory chain defects in patients with lacticacidemia. 217 27

Patients treated for aneurysmal subarachnoid hemorrhage show, in the long-term follow up, an elevated rate of cognitive disturbances that are mainly related to the impact of the initial bleeding: the neurotoxic effects of blood deposition in subarachnoidal spaces may result in a diffuse encephalopathy, but the intrinsic mechanism and the biochemical correlates are not known. In the present study we have evaluated mitochondrial function after experimental induction of subarachnoid hemorrhage. Mitochondrial function was evaluated in four different rat brain areas (frontal cortex, occipital cortex, hippocampus, and brain stem) after experimental isobaric subarachnoid hemorrhage in rats. Subarachnoid hemorrhage was induced by injecting 0.07 mL of arterial autologous blood into the cisterna magna. Intracranial pressure did not significantly increase. The nonsynaptic mitochondrial fraction was isolated from different rat brain areas, and the maximal rate of enzymatic reactions of some key enzymatic activities related to the Krebs cycle [nicotinamide adenine dinucleotide (oxidized form) (NAD+)-isocitrate dehydrogenase, citrate synthase, and succinate dehydrogenase] and of the electron transfer chain (cytochrome oxidase) were evaluated. The nonsynaptic mitochondrial fraction was utilized also to check parameters related to the mitochondrial respiration: state 3, state 4, uncoupled state, respiratory control ratio, and adenosine 5'-diphosphate/oxygen ratio. The biochemical parameters were measured at 1 and 72 hours after the subarachnoidal injection of blood. Subarachnoid hemorrhage did not affect the mitochondrial enzymatic activities both at 1 and 72 hours, while the mitochondrial enzymatic activities parameters were significantly affected: in particular, a significant decrease of respiratory control ratio in all tested brain areas was demonstrated. The increased mitochondrial vulnerability in the delayed phases could be one of the biochemical correlates of post-hemorrhagic encephalopathy.
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PMID:Experimental isobaric subarachnoid hemorrhage: regional mitochondrial function during the acute and late phase. 221 48

Electron microscopic examination of muscle specimens taken at biopsy in 6 patients with complex I deficiency and 1 patient with an unknown primary chemical defect who had the clinical characteristics of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) revealed striking abnormalities in blood vessels in 5. Abnormalities consisted of an increased number of enlarged mitochondria with complicated cristae in the pericytes of capillaries, endothelial cells, and smooth muscle cells of the small arteries, including terminal arterioles and precapillary sphincters, predominantly in smooth muscle cells. On statistical analysis, the number of mitochondria and the ratio of mitochondrial area to the total area of the smooth muscle cells were increased approximately tenfold (p less than 0.001). Although stroke-like episodes were not present, similar mitochondrial abnormalities in blood vessels were found in 1 patient who had the encephalomyopathic form of complex IV deficiency and in 2 patients in whom the primary chemical defects could not be clearly defined. Such abnormalities in small arteries might be responsible for the occasional occurrence of transient cerebral ischemia causing stroke-like episodes and progressive mental deterioration.
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PMID:Vascular involvement in mitochondrial myopathy. 250 Aug 89

Tissues and cultured fibroblasts from two patients with Leigh syndrome (subacute necrotizing encephalopathy) were examined. A systemic defect in cytochrome oxidase was identified by enzyme assay and estimation of cytochrome concentrations. Immunochemical analysis showed a reduction of most subunits of the cytochrome oxidase complex. The rate of synthesis of cytochrome oxidase subunits, determined by labelling experiments in cultured fibroblasts, was the same in the patients and normal controls. The reduced cytochrome oxidase content of the patients' tissues must therefore result from abnormal turnover of the protein subunits.
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PMID:Cytochrome c oxidase deficiency in subacute necrotizing encephalopathy (Leigh syndrome). 255 45

Identical twins developed myoclonic epilepsy in their teens. One twin remained mildly affected but the other went on to develop sensorineural deafness and ataxia with lactic acidosis and ragged red fibres leading to a diagnosis of mitochondrial encephalopathy. Multiple stroke-like episodes with hemiparesis followed, indicating progression from a MERRF to a MELAS phenotype. Biochemical studies revealed a severe deficiency of mitochondrial NADH-ubiquinone reductase and a moderate deficiency of cytochrome aa3. Western immunoblotting experiments using polyclonal antibodies raised against human placental cytochrome oxidase identified a similar profile of bands to those seen in controls, supporting the view that cytochrome aa3 deficiency in this case may be a secondary consequence of a failure of assembly related to a severe proximal respiratory chain defect.
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PMID:Progression from MERRF to MELAS phenotype in a patient with combined respiratory complex I and IV deficiencies. 285 17

On the basis of the known predilection of the auditory brainstem pathway for bilirubin toxicity, we have examined auditory brainstem responses of neonates during the period of hyperbilirubinemia. The auditory brainstem responses of 24 infants with serum bilirubin values between 15 to 25 mg/dL were compared with the responses of 19 infants without hyperbilirubinemia, who had similar gestational and postnatal ages. Wave IV-V complex was absent in at least one recording of 10/24 jaundiced infants, whereas wave complex IV-V was consistently present in all of the 19 infants without hyperbilirubinemia (P less than .001). Jaundiced infants also had prolonged brainstem transmission time (P less than .01) which reflected increased latency at both lower and upper brainstem levels. The above changes were rapidly reversed in the majority of instances. Neonatal jaundice was associated with significant transient aberrations of auditory brainstem responses, suggestive of a transient brainstem encephalopathy. This evidence of bilirubin entry to the brain at conventionally acceptable serum concentrations raises questions about current concepts of the mechanism of transfer of bilirubin across the blood-brain barrier.
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PMID:Auditory nerve-brainstem evoked responses in hyperbilirubinemic neonates. 663 69

The mitochondrial tRNALeu(UUR) A-->G(3243) mutation was identified in 22 unrelated patients. The probands and their relatives were assessed clinically and by quantitative mitochondrial DNA (mtDNA) analysis. While 10 probands had clinical features consistent with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), usually associated with this mutation, 12 probands had other phenotypes including other encephalopathies, chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy and ragged red fibres (MERRF), myopathy alone and diabetes and deafness. Histochemical analyses of muscle biopsies showed a higher proportion of cytochrome oxidase (COX) negative fibres, but fewer strongly COX reactive fibres, in patients with CPEO compared with those with MELAS. The proportion of mutant mtDNA present in blood was significantly greater in symptomatic than asymptomatic subjects, and was correlated with age in both. This correlation was not observed in patients with the tRNALys A-->G(8344) mutation. The proportion of mutant mtDNA A-->G(3243) in muscle was always greater than that in blood. Significant correlations between proportion of mutant mtDNA in blood and both age of onset of disease and a clinical severity score were observed. However, the proportion of mutant mtDNA in blood in affected and unaffected cases overlapped, preventing use of the genetic-clinical correlation for prognostic or predictive purposes. The presence of intrafamilial clustering of phenotypes and the imperfect relationship between proportion of mutant mtDNA and the presence or absence of disease suggests that other factors may determine the phenotype. To investigate this possibility further, the tRNALeu(UUR) gene was sequenced in 23 probands and six relatives. In 28 patients the sequence was normal apart from the 3243 mutation, but in members of one family there was a homoplasmic T-->C transition at position 3290 which was not found in 140 controls or 50 other patients with mitochondrial myopathy. The family with this transition had high levels of mutant mtDNA A-->G(3243), with a unique phenotype of predominant skeletal myopathy, suggesting that this second base change in tRNALeu(UUR) may influence the clinical phenotype.
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PMID:The mitochondrial DNA transfer RNALeu(UUR) A-->G(3243) mutation. A clinical and genetic study. 760 89


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