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)

Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective beta-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 +/- 26 versus 425 +/- 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 +/- 0.6 versus 5.8 +/- 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 +/- 0.9 versus 5.6 +/- 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial Ca(2+) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients.
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PMID:Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy. 1249 38

In this study, we report the host genetic responses that characterize Trypanosoma cruzi-induced myocarditis in a murine model of infection and disease development. The mRNA species from the myocardium of infected mice were assessed using cDNA microarray technology at immediate early, acute, and chronic stages of infection. The immediate early reaction of the host to T. cruzi infection was marked by up-regulation of transcripts indicative of proinflammatory and interferon-induced immune responses. Following acute infection, overexpression of transcripts for extracellular matrix (ECM) proteins, possibly initiated in response to myocardial injuries by invading and replicating parasites, was suggestive of active reparative and remodeling reactions. Surprisingly, progression to the cardiac disease phase was associated with coordinated down-regulation of a majority (>70%) of the differentially expressed genes. Among the most repressed genes were the troponins, essential for contractile function of the myofibrils, and the genes encoding components of oxidative phosphorylation (OXPHOS) pathways. Reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and biochemical assays confirmed the microarray results and provided evidence for the deficiency of OXPHOS complex IV in the chagasic murine heart. We discuss the apparent role of OXPHOS dysfunction in the cardiac hypertrophic and remodeling processes with the development of chagasic cardiomyopathy (CCM).
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PMID:Profiling gene transcription reveals a deficiency of mitochondrial oxidative phosphorylation in Trypanosoma cruzi-infected murine hearts: implications in chagasic myocarditis development. 1285 16

Rare cases of suspected spinal muscular atrophy (SMA) have been found to have cytochrome c oxidase (COX) deficiency. To date, four cases with SMA features have been reported in children with mutations in the synthesis of cytochrome oxidase 2 (SCO2) gene. We report a male neonate who was born hypotonic, with persistent lactic acidosis, spontaneous activity with EMG testing, development of respiratory distress in the first few hours of life, and died at 30 days of age with progressive cardiomyopathy. Testing for survival motor neurone (smn) and NAIP deletions were negative and a skeletal muscle biopsy showed neurogenic features with severe reductions of COX enzymatic and histochemical staining intensity. Post-mortem muscle, heart, and liver biopsies showed severe, moderate, and mild reductions in COX activity, respectively, with parallel findings in the protein content for the mitochondrial DNA (COII) and nuclear DNA (COIV) encoded subunits. DNA sequencing of exon 2 of the SCO2 gene revealed compound heterozygosity with mutations at G1541A (common mutation, E140K) and also at a novel site in the copper binding region (G1521A in the current case (converting a highly conserved cysteine to tyrosine [corrected] (C133Y) [corrected]); mother heterozygous for G1521A; and father heterozygous for G1541A). This case provides strong support that SCO2 mutations can result in neonatal hypotonia with an SMA 1 phenotype. SCO2 mutations should be screened in suspected SMA cases with normal smn mutation analysis and any one of; cardiomyopathy, lactic acidosis, or COX deficiency in muscle.
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PMID:Novel SCO2 mutation (G1521A) presenting as a spinal muscular atrophy type I phenotype. 1499 43

The A8344G mitochondrial DNA (mtDNA) mutation is best known for the MERRF phenotype (myoclonic epilepsy, myopathy, and ragged red fibers). We describe a sporadic case of an infant with the A8344G mtDNA mutation who presented with failure to thrive and sudden unexpected death at 11 months of age. The autopsy revealed a histiocytoid cardiomyopathy, diffuse steatosis of the liver, and bilateral retinal hypoplasia. Electron micrographs of cardiac myocytes showed striking mitochondrial hyperplasia, dispersing the sarcomeres. Special stains of frozen heart muscle showed an absence of complex IV (cytochrome c oxidase) in many of the myocytes. Both complexes I and IV of the respiratory chain were reduced in cardiac muscle. The A8344G mtDNA mutation was detected in both liver and cardiac muscle tissue. To our knowledge, this is the first description of the A8344G mtDNA mutation presenting as a sporadic case of fatal infantile cardiomyopathy and the first occurrence of this mutation associated with histiocytoid cardiomyopathy.
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PMID:A case of sporadic infantile histiocytoid cardiomyopathy caused by the A8344G (MERRF) mitochondrial DNA mutation. 1516 43

Screening the mitochondrial DNA of a 64-year-old woman with mitochondrial myopathy revealed 76% of the tRNA(Leu(UUR)) A3302G mutation in muscle. Muscle of her affected son carried 96% mutated mitochondrial DNA. Both patients were biopsied twice, showing isolated complex I deficiency in the son's first biopsy, additional increased (within normal range) complex II + III activities in his second biopsy, combined complex I, II + III deficiency in mothers first biopsy and additional complex IV deficiency in her second biopsy. After a stay in the mountains, the son died of cardiac arrhythmia. The A3302G mutation has been reported before and is associated with mitochondrial myopathy and cardiorespiratory failure. Pathogenesis is explained by abnormal mtRNA processing, which was also reported for the adjacent C3303T mutation associated with cardiomyopathy and/or skeletal myopathy. Our findings suggest that a high mutation load of the A3302G mutation can lead to fatal cardiorespiratory failure, likely triggered by low environmental oxygen pressure and exercise.
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PMID:Increased risk for cardiorespiratory failure associated with the A3302G mutation in the mitochondrial DNA encoded tRNALeu(UUR) gene. 1535 26

Keshan disease (KD) is a potentially fatal form of cardiomyopathy (disease of the heart muscle) endemic in certain areas of China. From 1984 to 1986, a national comprehensive scientific investigation on KD in Chuxiong region of Yunnan Province in the southwest China was conducted. The investigation team was composed of epidemiologists, clinic doctors, pathologists, biochemists, biophysicists and specialists in ecological environment. Results of pathological, biochemical and biophysical as well as clinical studies showed: an obvious increase of enlarged and swollen mitochondria with distended crista membranes in myocardium from patients with KD; significant reductions in the activity of oxidative phosphorylation (succinate dehydrogenase, cytochrome oxidase, succinate oxidase, H(+)-ATPase) of affected mitochondria; decrease in CoQ, cardiolipin, Se and GSHPx activity, while obvious increase in the Ca2+ content. So, it was suggested that mitochondria are the predominant target of the pathogenic factors of KD. Before Chuxiong KD survey only a few cases of mitochondrial cardiomyopathy were studied. During the multidisciplinary scientific investigation on KD in Chuxiong a large amount of samples from KD cases and the positive controls were examined. On the basis of the results obtained it was suggested that KD might be classified as a "Mitochondrial Cardiomyopathy" endemic in China. This is one of the achievements in the three years' survey in Chuxiong and is valuable not only to the deeper understanding of pathogenic mechanism of KD but also to the study of mitochondrial cardiomyopathy in general. Keshan disease is not a genetic disease, but is closely related to the malnutrition (especially microelement Se deficiency). KD occurs along a low Se belt, and Se supplementation has been effective in prevention of such disease. The incidence of KD has sharply decreased along with the steady raise of living standard and realization of preventive measures. At present, patients of KD are very sparse. In recent years the research on the non-KD mitochondrial cardiomyopathy has progressed rapidly. Given the advances in this aspect a minireview is written to evaluate the classification of KD as a kind of mitochondrial cardiomyopathy.
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PMID:Keshan disease and mitochondrial cardiomyopathy. 1731 89

Mitochondrial Ca(2+) plays important roles in the regulation of energy metabolism and cellular Ca(2+) homeostasis. In this study, we characterized mitochondrial Ca(2+) accumulation in Syrian hamster hearts with hereditary cardiomyopathy (strain BIO 14.6). Exposure of isolated mitochondria from 70 nM to 30 microM Ca(2+) ([Ca(2+)](o)) caused a concentration-dependent increase in intramitochondrial Ca(2+) concentrations ([Ca(2+)](m)). The [Ca(2+)](m) was significantly lower in cardiomyopathic (CMP) hamsters than in healthy hamsters when [Ca(2+)](o) was higher than 1 microM and a decrease of about 52% was detected at [Ca(2+)](o) of 30 microM (916 +/- 67 nM vs 1,932 +/- 132 nM in control). A possible mechanism responsible for the decreased mitochondrial Ca(2+) uptake in CMP hamsters is the depolarization of mitochondrial membrane potential (Delta psi (m)). Using a tetraphenylphosphonium (TPP(+)) electrode, the measured Delta psi (m) in failing heart mitochondria was -136 +/- 1.5 mV compared with -159 +/- 1.3 mV in controls. Analyses of mitochondrial respiratory chain demonstrated a significant impairment of complex I and complex IV activities in failing heart mitochondria. In summary, a less negative Delta psi (m) resulting from defects in the respiratory chain may lead to attenuated mitochondrial Ca(2+) accumulation, which in turn may contribute to the depressed energy production and myocardial contractility in this model of heart failure. In addition to other known impairments of ion transport in sarcoplasmic reticulum and plasma membrane, results from this paper on mitochondrial dysfunctions expand our understanding of the molecular mechanisms leading to heart failure.
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PMID:Mechanisms of reduced mitochondrial Ca2+ accumulation in failing hamster heart. 1738 8

The G8363A is a very rare mtDNA tRNA(Lys) gene mutation that has been associated to MERRF-like syndrome, cardiomyopathy or Leigh syndrome. Here, we describe the clinical and molecular features of a new large multigenerational family and we review the literature of cases with this mutation. In our family seven members presented a heterogeneous mitochondrial disease phenotype, from MERRF-like syndrome to isolated psychiatric disorder, associated with the G8363A mutation. The two probands are dizygotic twin sisters affected by mental retardation, neural deafness, myopathy, myoclonic epilepsy and ataxia. Twins' muscle biopsies showed a severe cytochrome c oxidase (COX) deficiency and ragged-red fibers. Their mitochondrial respiratory chain was defective in complexes I and IV in muscle. A severe reduction in complex IV activity was also observed in fibroblasts and myoblasts. Molecular analysis showed a G8363A transition in the mtDNA tRNA(Lys) gene. The mutation was almost homoplasmic (>90%) in muscle and blood of the twins and heteroplasmic (55+/-8%) in blood sample from affected maternal relatives. Based on our family data and the meta-analysis of the literature, we confirm that mutational load directly correlates with severity of the disease (severe vs mild/moderate phenotype; P=0.00168) and with disease onset (P<0.00001). However the presence of several exceptions and overlaps among patients with different clinical severity limits the clinical usefulness of this observation. Although the pathogenicity of the G8363A mutation is well established, counselling is a difficult task for clinicians because of the large phenotypical variability. Our study contributes further data on the clinical spectrum and its relation with the level of G8363A tRNA(Lys) mtDNA mutation.
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PMID:Mitochondrial DNA G8363A mutation in the tRNA Lys gene: clinical, biochemical and pathological study. 1927 89

Life-threatening cardiomyopathy is associated with certain systemic myopathies and usually presents as an end-stage progression of the disease. However, cardiac symptoms can sometimes precede muscle weakness. The authors reviewed medical records from 2003 to 2008 on patients attending their neuromuscular clinic and identified patients who initially presented with an end-stage cardiomyopathy and were later diagnosed with a specific muscle disease through muscle biopsy. They report 5 cases of children who initially presented with cardiomyopathies without neuromuscular symptoms. The cardiac symptoms were so severe that 4 of them required cardiac transplantation and 1 died prior to transplantation. Review of muscle pathology confirmed the diagnoses of Becker muscular dystrophy, myofibrillar myopathy, mitochondrial myopathy with cytochrome oxidase deficiency, Danon disease, and glycogen storage disease. The authors conclude that cardiomyopathy can be the initial presentation of a wide spectrum of systemic myopathies. Careful evaluation of neuromuscular systems should be carried out in patients presenting with end-stage cardiomyopathies.
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PMID:End-stage cardiac disease as an initial presentation of systemic myopathies: case series and literature review. 2044 93

The assembly of mitochondrial respiratory chain complex IV (cytochrome c oxidase) involves the coordinated action of several assembly chaperones. In Saccharomyces cerevisiae, at least 30 different assembly chaperones have been identified. To date, pathogenic mutations leading to a mitochondrial disorder have been identified in only seven of the corresponding human genes. One of the genes for which the relevance to human pathology is unknown is C2orf64, an ortholog of the S. cerevisiae gene PET191. This gene has previously been shown to be a complex IV assembly factor in yeast, although its exact role is still unknown. Previous research in a large cohort of complex IV deficient patients did not support an etiological role of C2orf64 in complex IV deficiency. In this report, a homozygous mutation in C2orf64 is described in two siblings affected by fatal neonatal cardiomyopathy. Pathogenicity of the mutation is supported by the results of a complementation experiment, showing that complex IV activity can be fully restored by retroviral transduction of wild-type C2orf64 in patient-derived fibroblasts. Detailed analysis of complex IV assembly intermediates in patient fibroblasts by 2D-BN PAGE revealed the accumulation of a small assembly intermediate containing subunit COX1 but not the COX2, COX4, or COX5b subunits, indicating that C2orf64 is involved in an early step of the complex IV assembly process. The results of this study demonstrate that C2orf64 is essential for human complex IV assembly and that C2orf64 mutational analysis should be considered for complex IV deficient patients, in particular those with hypertrophic cardiomyopathy.
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PMID:A mutation in C2orf64 causes impaired cytochrome c oxidase assembly and mitochondrial cardiomyopathy. 2145 8


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