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)

We reported a girl with mitochondrial encephalomyopathy, who had various neuromuscular symptoms including dilated cardiomyopathy, generalized convulsions, myoclonus, muscular weakness and growth retardation. Lactate levels in the serum and CSF were elevated. Muscle biopsy showed scattered ragged-red fibers, and complex I (NADH-CoQ reductase) and complex IV (cytochrome c oxidase) were markedly reduced. Although she was treated with coenzyme Q, DL-carnitine and sodium succinate, she died of progressive congestive heart failure at 9 10/12 years of age.
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PMID:[A case of mitochondrial encephalomyopathy with cardiomyopathy due to decreased complex I and IV activities]. 255 57

The results of laboratory investigations in concerning 15 patients suspected of mitochondrial disease (MD) are presented. Our purpose is to provide an outline of the investigative modalities that support the clinical suspicion and have been found to be useful in the diagnosis. Five clinical groups were studied including 5 exercise intolerances (2 with inflammatory myopathy), 3 with myopathies (1 with dilated cardiomyopathy), 2 with progressive external oftalmoplegia (1 associated with cerebellar ataxia+epilepsy+hypertrophic cardiomyopathy+pes cavus), 4 with encephalopathies (3 with myoclonic encephalopathies with ataxia and dementia and 1 with epilepsy and tremor), and 1 with metabolic acidosis and cardiomyopathy. We used the following categories of investigative procedures: clinical phenotype analysis including pedigree study, neurophysiological tests, bicycle ergometric evaluation, neuroimaging, microscopic study of skeletal muscle biopsy, post-mortem examination, biochemical assays and molecular genetic studies. EMG showed myopathic changes in 5 cases, features of neuropathy in 2, mixed myopathic and neuropathic pattern in 1 and nonspecific changes in 3. EMG was normal in 3 patients. The most common skeletal muscle abnormalities were variation in fiber size (60%), lipid inclusions (33.3%), oxidative subsarcolemmal aggregates (26.7%) and ragged-red fibers (26.7%). Electron microscopy revealed mitochondrial abnormalities in 8 out of 14 patients' muscle biopsies, and in myocardiac and hepatic tissues of another. Site of biochemical defect was located in 12 patients. Complex I defect in 6, complexes I+IV deficiencies in 3, complex II defect in 1, complex IV deficiency in 1, complexes II+IV deficiencies in 1, and complex III defect in 1. In 2 patients the biochemical defect was not located. Mitochondrial DNA alterations were not found in 7 investigated patients. The clinical spectrum of MD has become increasingly wider. After the clinica suspicion, the diagnosis depends up on the appropriate use of skeletal muscle biopsy, biochemical investigations and molecular genetic techniques. Conventional EMG and automatic measurement of the electromyogram are particularly helpful in confirming the clinical suspicion in patients with predominantly central nervous system disease or in cases in which clinical signs are few.
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PMID:[Clinical and investigative approaches in mitochondrial diseases. A review of 15 cases]. 780 49

Previous studies of cytochrome c oxidase (complex IV of the respiratory chain) in the heart of a 26-year-old man with longstanding Kearns-Sayre syndrome and fatal congestive cardiomyopathy had revealed the presence of randomly distributed enzyme-deficient cardiomyocytes, both in the contractile and the conducting myocardium. In the present study, the conduction system of the heart was screened for the occurrence of the common 4977 base pair deletion (8, 482-13, 459) of mitochondrial DNA (mtDNA) in formalin-fixed, paraffin-embedded tissue and compared with the contractile myocardium. Polymerase chain reaction analysis revealed that in the sinus node, the atrioventricular node, and the bundle branches, 35 to 40% of total mtDNA molecules harbored the common deletion. In contrast, in the contractile myocardium, 10 to 20% of total mtDNA was deleted (P = .05). These results demonstrate that in Kearns-Sayre syndrome, the conduction system of the heart preferentially accumulates the common deletion. This finding might help to explain the high prevalence of cardiac dysrhythmias in this syndrome.
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PMID:The common 4977 base pair deletion of mitochondrial DNA preferentially accumulates in the cardiac conduction system of patients with Kearns-Sayre syndrome. 952 79

An Argentine male child died at 4.5 years of age of a lethal mitochondrial disease associated with a MELAS mutation and a Barth syndrome-like presentation. The child had severe failure to thrive from the early months and for approximately two years thereafter. In addition, the patient had severely delayed gross motor milestones, marked muscle weakness, and dilated cardiomyopathy that progressed to congestive heart failure. He also had persistently elevated urinary levels of 3-methylglutaconic and 2-ethylhydracrylic acids and low blood levels of cholesterol. Detailed histopathologic evaluation of the skeletal muscle biopsy showed high activity of succinate dehydrogenase, a generalized decrease of COX activity, and abundant ragged-red fibers. Electron microscopic studies revealed multiple mitochondrial abnormalities in lymphocytes and monocytes, in the striated muscle, and in the postmortem samples (muscle, heart, liver, and brain). Biochemical analysis showed a pronounced and constant lactic acidosis, and abnormal urinary organic acid excretion (unchanged in the fasting and postprandial states). In addition, in CSF there was a marked increase of lactate and beta-hydroxybutyrate (beta-HOB) and also a high systemic ratio beta-HOB/acetoacetate. Enzymatic assay of the respiratory chain in biopsied muscle showed 10% of complex I activity and 24% of complex IV activity compared with controls. Molecular studies of the mitochondrial genome revealed an A to G mutation at nucleotide pair 3243 in mitochondrial DNA, a well-known pathogenetic mutation (MELAS mutation) in all the patient's tissues and also in the blood specimens of the probands mother and sibs (4 of 5). The diagnosis of MELAS mutation was reinforced by the absence of an identifiable mutation in the X-linked G4.5 gene of the propositus. The present observation gives additional evidence of the variable clinical expression of mtDNA mutations in humans and demonstrates that all clinical variants deserve adequate investigation to establish a primary defect. It also suggests adding Barth-like syndrome to the list of phenotypes with the MELAS mutation.
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PMID:Barth's syndrome-like disorder: a new phenotype with a maternally inherited A3243G substitution of mitochondrial DNA (MELAS mutation). 1124 64

Cardiolipin (CL) is recognized to be an essential phospholipid in eukaryotic energy metabolism so that physiological and pathological perturbations in its synthetic and catabolic pathways play key roles in maintaining mitochondrial structure and function, and ultimately cell survival. This review describes potential regulatory mechanisms in CL synthesis and the effects of de-acylation pathways on steady state levels of CL and its interaction with cytochrome c. The latter interaction is significant in the initiation of programmed cell death. Physiological factors that modify CL acylation include ageing, dietary influences and ischemia/reperfusion where the terminal events may be either necrosis or apoptosis. In various pathologies, phospholipase activity increases in response to production of peroxidized CL. The cell may use lysosomal or mitochondrial pathways for CL degradation. However, the manner by which CL and cytochrome c leave the mitochondria is not well understood. The lipid (CL)-bound form of cytochrome c is thought to initiate apoptosis via a lipid transfer step involving mitochondrially targeted Bid. A direct relationship between CL loss and cytochrome c release from the mitochondria has been identified as an initial step in the pathway to apoptosis. An absolute requirement for CL in the function of crucial mitochondrial proteins, e.g., cytochrome oxidase and the adenine nucleotide translocase, are likely additional factors impacting apoptosis and cellular energy homeostasis. This is reflected in the occurrence of both oncotic and apoptotic events in ischemia and reperfusion injury. Other potential clinical manifestations of perturbations of CL synthesis are discussed with particular emphasis on Barth Syndrome where a primary defect can be attributed to CL metabolism and is associated with dilated cardiomyopathy. Finally, the model of fatty acid induced apoptosis is used as a paradigm to our understanding of the temporal relationship between decreased mitochondrial CL, release of cytochrome c, and initiation of apoptosis.
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PMID:Cardiolipin and apoptosis. 1253 42

Identification of factors regulating cardiomyocyte survival and growth is important to understand the pathogenesis of congenital heart diseases. Little is known about the molecular mechanism of cardiac functions triggered by serotonin. The link between signaling circuitry of external stimuli and the mitochondrial apoptotic machinery is of wide interest in cardiac diseases. Using cultured cardiomyocytes and 5-hydroxytryptamine (5-HT)2B-receptor knockout mice as an animal model of dilated cardiomyopathy, for the first time we show that serotonin via the Gq-coupled 5-HT2B-receptor protect cardiomyocytes against serum deprivation-induced apoptosis as manifested by DNA fragmentation, nuclear chromatin condensation, and TUNEL labeling. Serotonin prevents cytochrome c release and caspase-9 and -3 activation after serum deprivation via cross-talks between phosphatidylinositol-3 kinase/Akt and extracellular signal-regulated kinase (ERK) 1/2 signaling pathways. Serotonin binding to 5-HT2B-receptor activates ERK kinases to inhibit Bax expression induced by serum deprivation. Serotonin via phosphatidylinositol-3 kinase/Akt can activate NF-kappaB that is required for the regulation of the mitochondrial adenine nucleotide translocator (ANT-1). Parallel to these observations, ultrastructural analysis in the 5-HT2B-receptor knockout mice heart revealed pronounced mitochondrial defects in addition to altered mitochondrial enzyme activities (cytochrome oxidase and succinate dehydrogenase) and ANT-1 and Bax expressions. These findings identify 5-HT as a novel survival factor targeting mitochondria in cardiomyocytes.
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PMID:Serotonin is a novel survival factor of cardiomyocytes: mitochondria as a target of 5-HT2B receptor signaling. 1273 97

The mitochondrial phospholipid cardiolipin is required for optimal mitochondrial respiration. In this study, cardiolipin molecular species and cytochrome oxidase (COx) activity were studied in interfibrillar (IF) and subsarcolemmal (SSL) cardiac mitochondria from Spontaneously Hypertensive Heart Failure (SHHF) and Sprague-Dawley (SD) rats throughout their natural life span. Fisher Brown Norway (FBN) and young aortic-constricted SHHF rats were also studied to investigate cardiolipin alterations in aging versus pathology. Additionally, cardiolipin was analyzed in human hearts explanted from patients with dilated cardiomyopathy. A loss of tetralinoleoyl cardiolipin (L(4)CL), the predominant species in the healthy mammalian heart, occurred during the natural or accelerated development of heart failure in SHHF rats and humans. L(4)CL decreases correlated with reduced COx activity (no decrease in protein levels) in SHHF cardiac mitochondria, but with no change in citrate synthase (a matrix enzyme) activity. The fraction of cardiac cardiolipin containing L(4)CL became much lower with age in SHHF than in SD or FBN mitochondria. In summary, a progressive loss of cardiac L(4)CL, possibly attributable to decreased remodeling, occurs in response to chronic cardiac overload, but not aging alone, in both IF and SSL mitochondria. This may contribute to mitochondrial respiratory dysfunction during the pathogenesis of heart failure.
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PMID:Loss of cardiac tetralinoleoyl cardiolipin in human and experimental heart failure. 1742 48

Dilated cardiomyopathy is a rare complication in propionic acidaemia (PA). Underlying pathophysiological mechanisms are poorly understood. We present a child of Pakistani consanguineous parents, diagnosed with late-onset PA at 18months of age. He presented a mild phenotype, showed no severe further decompensations, normal growth and psychomotor development on a low protein diet and carnitine supplementation. At 15years, a mildly dilated left ventricle was noticed. At 17years he presented after a 2-3month history of lethargy and weight loss with severe decompensated dilated cardiomyopathy. He was stabilised on inotropic support and continuous haemofiltration; a Berlin Heart biventricular assist device was implanted. He received d,l-hydroxybutyrate 200mg/kg/day, riboflavin and thiamine 200mg/day each and coenzyme Q10 (CoQ10). Myocardial biopsy showed endocardial fibrosis, enlarged mitochondria, with atypical cristae and slightly low respiratory chain (RC) complex IV activity relative to citrate synthase (0.012, reference range 0.014-0.034). Myocardial CoQ10 was markedly decreased (224pmol/mg, reference range 942-2738), with a marginally decreased white blood cell level (34pmol/mg reference range 37-133). The dose of CoQ10 was increased from 1.5 to 25mg/kg/day. Cardiomyopathy slowly improved allowing removal of the external mechanical cardiac support after 67days. We demonstrate for the first time low myocardial CoQ10 in cardiomyopathy in PA, highlighting secondary mitochondrial impairment as a relevant causative mechanism. According to these findings, a high-dose CoQ10 supplementation could be a potential adjuvant therapeutic to be considered in PA-related cardiomyopathy.
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PMID:Successful reversal of propionic acidaemia associated cardiomyopathy: evidence for low myocardial coenzyme Q10 status and secondary mitochondrial dysfunction as an underlying pathophysiological mechanism. 2501 Mar 87