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Query: UMLS:C0162671 (MELAS)
 587 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Respiratory function of mitochondria is compromised in aging human tissues and severely impaired in the patients with mitochondrial disease. A wide spectrum of mitochondrial DNA (mtDNA) mutations has been established to associate with mitochondrial diseases. Some of these mtDNA mutations also occur in various human tissues in an age-dependent manner. These mtDNA mutations cause defects in the respiratory chain due to impairment of the gene expression and structure of respiratory chain polypeptides that are encoded by the mitochondrial genome. Since defective mitochondria generate more reactive oxygen species (ROS) such as O2- and H2O2 via electron leak, we hypothesized that oxidative stress is a contributory factor for aging and mitochondrial disease. This hypothesis has been supported by the findings that oxidative stress and oxidative damage in tissues and culture cells are increased in elderly subjects and patients with mitochondrial diseases. Another line of supporting evidence is our recent finding that the enzyme activities of Cu,Zn-SOD, catalase and glutathione peroxidase (GPx) decrease with age in skin fibroblasts. By contrast, Mn-SOD activity increases up to 65 years of age and then slightly declines thereafter. On the other hand, we observed that the RNA, protein and activity levels of Mn-SOD are increased two- to three-fold in skin fibroblasts of the patients with CPEO syndrome but are dramatically decreased in patients with MELAS or MERRF syndrome. However, the other antioxidant enzymes did not change in the same manner. The imbalance in the expression of these antioxidant enzymes indicates that the production of ROS is in excess of their removal, which in turn may elicit an elevation of oxidative stress in the fibroblasts. Indeed, it was found that intracellular levels of H2O2 and oxidative damage to DNA and lipids in skin fibroblasts from elderly subjects or patients with mitochondrial diseases are significantly increased as compared to those of age-matched controls. Furthermore, Mn-SOD or GPx-1 gene knockout mice were found to display neurological disorders and enhanced oxidative damage similar to those observed in the patients with mitochondrial disease. These observations are reviewed in this article to support that oxidative stress elicited by defective respiratory function and impaired antioxidant enzyme system plays a key role in the pathophysiology of mitochondrial disease and human aging.
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PMID:Oxidative stress in human aging and mitochondrial disease-consequences of defective mitochondrial respiration and impaired antioxidant enzyme system. 1140 14

Most patients with mitochondrial disorders are diagnosed by finding a respiratory chain enzyme defect or a mutation in the mitochondrial DNA (mtDNA). The provision of accurate genetic counseling and reproductive options to these families is complicated by the unique genetic features of mtDNA that distinguish it from Mendelian genetics. These include maternal inheritance, heteroplasmy, the threshold effect, the mitochondrial bottleneck, tissue variation, and selection. Although we still have much to learn about mtDNA genetics, it is now possible to provide useful guidance to families with an mtDNA mutation or a respiratory chain enzyme defect. We describe a range of current reproductive options that may be considered for prevention of transmission of mtDNA mutations, including the use of donor oocytes, prenatal diagnosis (by chorionic villus sampling or amniocentesis), and preimplantation genetic diagnosis, plus possible future options such as nuclear transfer and cytoplasmic transfer. For common mtDNA mutations associated with mitochondrial cytopathies (such as NARP, Leigh Disease, MELAS, MERRF, Leber's Hereditary Optic Neuropathy, CPEO, Kearns-Sayre syndrome, and Pearson syndrome), we summarize the available data on recurrence risk and discuss the relative advantages and disadvantages of reproductive options.
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PMID:Mitochondrial disorders: genetics, counseling, prenatal diagnosis and reproductive options. 1157 29

More than 70 different point mutations in human mitochondrial tRNA genes are correlated with severe disorders, including fatal cardiopathies, encephalopathies, myopathies, and others. So far, investigation of the molecular impact(s) of mutations has focused on the affected tRNA itself by seeking structural and/or functional perturbations capable of interfering with synthesis of the 13 mitochondrion-encoded subunits of respiratory chain complexes. Here, a proteomic approach was used to investigate whether such mutations would affect the pattern of mitochondrial proteins at a broader level. Analysis of several hundred mitochondrial proteins from sibling cybrid cell lines by two-dimensional electrophoresis, an approach that takes into account all regulatory steps of mitochondrial and nuclear gene expression, indeed reveals a number of up- and downregulated proteins when healthy and single-point-mutation-carrying mitochondria representative of either MELAS or MERRF syndrome were compared. Assignment by mass spectrometry of the two proteins which exhibit obvious large quantitative decreases in the levels of both pathologic mitochondria identified nuclear-encoded subunits of cytochrome c oxidase, a respiratory chain complex. This clearly shows a linkage between the effects of mutations in mitochondrial tRNA genes and the steady-state level of nuclear-encoded proteins in mitochondria. It opens new routes toward a large-scale exploration of potential proteic partners involved in the genotype-phenotype correlation of mitochondrial disorders.
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PMID:Comparative proteomics as a new tool for exploring human mitochondrial tRNA disorders. 1177 11

Dysfunction in mitochondrial processes has been related to several pathologies. In these disorders, the cell suffers oxidative imbalance that is mostly due to defects in pyruvate metabolism, mitochondrial fatty acids oxidation, the citric acid cycle or electron transport by the mitochondrial respiratory chain. These metabolic alterations produce mitochondrial diseases that have been related to inherited syndromes, such as MERRF or MELAS. The main affected organs are brain, skeletal muscle, kidney, heart and liver, because of the high energetic demand and the oxidative metabolism. Moreover, the relationship between mitochondrial dysfunction and neurodegenerative processes, such as Parkinson disease or Alzheimer disease, as well as ageing, has been shown. Because mitochondrias are the target of several xenobiotics, such as aspirin, AZT or alcohol consumption, mitochondrial impairment has also been proposed as a mechanism of toxicity. Most laboratory tests that are available in the diagnosis of mitochondrial illness are assayed in tissue biopsies and are usually difficult to interpret. Recently, it has been shown that non-invasive techniques, such as nuclear magnetic resonance or the 2-keto[1-(13)C]isocaproic acid breath test, may be useful to assess mitochondrial function. This article attempts to show the laboratory approach to mitochondrial diseases, reviewing new techniques that could be of great value in the research of mitochondrial function, such as the 2-keto[1-(13)C]isocaproic breath test.
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PMID:Laboratory approach to mitochondrial diseases. 1180 Feb 89

Mitochondrial dysfunction should be considered in the differential diagnosis of any progressive multisystem disorder. The diagnosis is most challenging when only one symptom is present. In contrast, the diagnosis is easier to consider when two or more seemingly unrelated symptoms are present, involving more than one organ system. It is important to consider the diagnosis of a mitochondrial disorder when dealing with an unexplained association of symptoms, with an early onset and progressive course involving seemingly unrelated organs. The investigation can be relatively straightforward if a person has a recognizable phenotype and if it is possible to identify a known pathogenic mtDNA mutation. The difficulty arises when no known mtDNA defect can be found or when the clinical abnormalities are complex and not easily matched to those of more common mitochondrial disorders. In summary: A full mitochondrial evaluation often is warranted in children with a complex neurologic picture or a single neurologic symptom and other system involvement. When the presentation is classic for a maternally inherited mitochondrial syndrome, such as MELAS, MERRF, or Leber's hereditary optic neuropathy, appropriate mtDNA studies should be obtained first. When the clinical picture is classic for a nuclear DNA inherited syndrome and the gene or linkage is known, such as MNGIE, the clinician should proceed with genetic studies. When the clinical picture is nonspecific but highly suggestive of a mitochondrial disorder, the clinician should start with plasma or CSF lactic acid, ketone bodies, plasma acylcarnitines, and urinary organic acids. If these studies are abnormal, the clinician should proceed with muscle biopsy and assessment of the respiratory chain enzymes. Normal plasma or CSF lactic acid does not rule out a mitochondrial disorder.
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PMID:Diagnosis and management of mitochondrial diseases. 1182 5

A male infant developed progressive neuromuscular disease, hypertrophic cardiomyopathy and brain atrophy since the birth. Increased level of lactate with increased lactate/pyruvate ratio suggested a disturbance in the mitochondrial energy metabolism. The activities of respiratory chain complexes III, IV and II + III, of pyruvate dehydrogenase complex and of citrate synthase in isolated muscle mitochondria were low in comparison with controls, with parallel decrease in the content of protein amount of respiratory chain complexes III and IV. No large scale deletions of mitochondrial DNA (mtDNA) and mtDNA point mutations A3243G, A8344G or T8993G indicating syndromes MELAS, MERRF or NARP were detected. The boy died at the age of 7 weeks. The autopsy revealed typical changes of mitochondrial cardiomyopathy-marked myocardial hypertrophy with muscle pallor, histological finding of diffuse fine granularity of the cytoplasm in the perinuclear regions, and ultrastructural findings of mitochondrial hyperplasia, enlargement (megamitochondria) and abnormal shape.
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PMID:Mitochondrial cardiomyopathy--case report. 1193 62

Four members of a family were found to carry the A3243G mtDNA mutation. Clinical features varied from typical MELAS to myoclonic epilepsy to simple deafness without neurological signs. Several other members of the family had symptoms consistent with a mitochondrial disease. Muscle biopsy in 3 of the 4 patients showed the most prominent mitochondrial alterations with partial deficiency of cytochrome c oxidase in the case with the mildest phenotype. Mitochondrial DNA analysis detected a variable percentage of A3243G mutation, roughly correlating with the phenotype. The interesting feature of the family lies in the great intrafamilial variability of the severity of clinical expression, encompassing MELAS and MERRF features, associated with the A3243G mtDNA mutation. A search for the most common mtDNA mutations is recommended in all patients featuring incomplete MELAS or MERRF syndromes and in all familial cases presenting minimal clinical signs.
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PMID:MERRF/MELAS overlap syndrome in a family with A3243G mtDNA mutation. 1200 55

Over the past few years, many studies have been done on the apoptotic involvement in muscle fiber degeneration in various myopathies, but the occurrence of apoptosis in muscles of mitochondrial encephalomyopathies is still controversial. To confirm whether apoptotic processes are truly related to muscle fiber degeneration in mitochondrial encephalomyopathies, we performed the TUNEL method not only at the light microscopic (LM) but also at the electron microscopic (EM) level for muscles of five MELAS, five CPEO and five MERRF patients and five control muscles. Immunohistochemical studies of Bcl-2, Bax, cytochrome c, Apaf-1, activated caspase-3 and human inhibitor of apoptosis protein XIAP, and immunoblotting of Apaf-1 and XIAP were also carried out. In LM-TUNEL, MELAS, CPEO and MERRF patients had only very small numbers of TUNEL-positive myonuclei: 0.13+/-0.10%, 0.15+/-0.14% and 0.04+/-0.09%, respectively. Almost all of them were seen in ragged-red fibers (RRFs). EM-TUNEL showed no significant increase of DNA fragmentation in RRFs despite mild peripheral chromatin condensation. However, Bax and Apaf-1 expression and cytochrome c release from mitochondria were seen in RRFs. Caspase-3 activation was confirmed in 9.0+/-3.7%, 12.0+/-4.4% and 12.4+/-3.8% of RRFs in MELAS, CPEO and MERRF, respectively, but not in control muscles. Almost all RRFs showed sarcoplasmic expression of XIAP. Thus, there is a possibility that, although apoptotic reactions started in muscles of mitochondrial encephalomyopathies, their execution is rarely completed. Sarcoplasmic expression of XIAP probably leads to the suspension of the apoptotic process in mitochondrial encephalomyopathies.
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PMID:Apoptosis is suspended in muscle of mitochondrial encephalomyopathies. 1201 84

The mitochondrial cytopathies are genetically and phenotypically heterogeneous group of disorders caused by structural and functional abnormalities in mitochondria. To the best of our knowledge, there are very few studies published from India till date. Selected and confirmed fourteen cases of neurological mitochondrial cytopathies with different clinical syndromes admitted between 1997 and 2000 are being reported. There were 8 male and 6 female patients. The mean age was 24.42+/-11.18 years (range 4-40 years). Twelve patients could be categorized into well-defined syndromes, while two belonged to undefined group. In the defined syndrome categories, three patients had MELAS (mitochondrial encephalopathy, lactic acidosis and stroke like episodes), three had MERRF (myoclonic epilepsy and ragged red fibre myopathy), three cases had KSS (Kearns-Sayre Syndrome) and three were diagnosed to be suffering from mitochondrial myopathy. In the uncategorized group, one case presented with paroxysmal kinesogenic dystonia and the other manifested with generalized chorea alone. Serum lactic acid level was significantly increased in all the patients (fasting 28.96+/-4.59 mg%, post exercise 41.02+/-4.93 mg%). Muscle biopsy was done in all cases. Succinic dehydrogenase staining of muscle tissue showed subsarcolemmal accumulation of mitochondria in 12 cases. Mitochondrial DNA study could be performed in one case only and it did not reveal any mutation at nucleotides 3243 and 8344. MRI brain showed multiple infarcts in MELAS, hyperintensities in putaminal areas in chorea and bilateral cerebellar atrophy in MERRF.
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PMID:Neurological mitochondrial cytopathies. 1213 80

Taurine (2-aminoethanesulphonic acid), a naturally occurring, sulfur-containing amino acid, is found at high concentrations in mammalian plasma and tissues. Although taurine is involved in a variety of processes in humans, it has never been found as a component of a protein or a nucleic acid, and its precise biochemical functions are not fully understood. Here, we report the identification of two novel taurine-containing modified uridines (5-taurinomethyluridine and 5-taurinomethyl-2-thiouridine) in human and bovine mitochondrial tRNAs. Our work further revealed that these nucleosides are synthesized by the direct incorporation of taurine supplied to the medium. This is the first reported evidence that taurine is a constituent of biological macromolecules, unveiling the prospect of obtaining new insights into the functions and subcellular localization of this abundant amino acid. Since modification of these taurine-containing uridines has been found to be lacking in mutant mitochondrial tRNAs for Leu(UUR) and Lys from pathogenic cells of the mitochondrial encephalomyopathies MELAS and MERRF, respectively, our findings will considerably deepen our understanding of the molecular pathogenesis of mitochondrial encephalomyopathic diseases.
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PMID:Taurine as a constituent of mitochondrial tRNAs: new insights into the functions of taurine and human mitochondrial diseases. 1245 64


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