Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytoplasts from two unrelated patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) harboring an A----G transition at nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome were fused with human cells lacking endogenous mitochondrial DNA (mtDNA) (rho 0 cells). Selected cybrid lines, containing less than 15 or greater than or equal to 95% mutated genomes, were examined for differences in genetic, biochemical, and morphological characteristics. Cybrids containing greater than or equal to 95% mutant mtDNA, but not those containing normal mtDNA, exhibited decreases in the rates of synthesis and in the steady-state levels of the mitochondrial translation products. In addition, NADH dehydrogenase subunit 1 (ND 1) exhibited a slightly altered mobility on polyacrylamide gel electrophoresis. The mutation also correlated with a severe respiratory chain deficiency. A small but consistent increase in the steady-state levels of an RNA transcript corresponding to 16S rRNA + tRNA(Leu(UUR)) + ND 1 genes was detected. However, there was no evidence of major errors in processing of the heavy-strand-encoded transcripts or of altered steady-state levels or ratios of mitochondrial rRNAs or mRNAs. These results provide evidence for a direct relationship between the tRNALeu(UUR) mutation and the pathogenesis of this mitochondrial disease.
Mol Cell Biol 1992 Feb
PMID:Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. 173 28

Rats were injected intraperitoneally with HgCl2 at doses of 2.5, 5, 7.5, and 10 mumol of Hg/kg. Urine was collected over a 24-hr period. At this time, plasma samples were taken and kidney damage was assessed by histological examination. Urinary gamma-glutamyltransferase levels were significantly elevated at Hg2+ doses of 7.5 and 10 mumol/kg, consistent with the detection of acute tubular necrosis by light microscopy. Resonances for a large number of low molecular weight metabolites were assigned in high resolution 1H NMR spectra of rat urine. Spectra from small volumes of urine (about 0.5 ml) were obtained in less than 5 min with no pretreatment. Significant Hg2+ dose-related decreases in the excretion of creatinine and citrate and increases of glucose, glycine, alanine, alpha-ketoglutarate, succinate, and acetate were detected. Elevated levels of lactate and creatinine in plasma of rats receiving the two highest doses were found by 1H NMR. There was a good correspondence between the histopathology, enzyme excretion, and 1H NMR urinary metabolite fingerprints in the assessment of Hg2+-induced renal damage. 1H NMR provided a sensitive measure of mercury-induced nephrotoxic lesions, and information on the molecular basis of mercury cytotoxicity was derived from the abnormal patterns of metabolite excretion. These suggested that primary metabolic effects of mercury were upon mitochondrial metabolism, in particular inhibition of certain citric acid cycle enzymes leading to decreased utilization of alpha-ketoglutarate and succinate by the renal tubular cells. The decrease in urinary citrate associated with Hg2+ dosing was attributed to intracellular, tubular acidosis with concomitant enhanced citrate reabsorption. The acidosis was assumed to arise from a combination of the inhibition of tubular carbonic anhydrase and a mild metabolic lactic acidosis due to increased activity of anaerobic pathways in the kidney. The possible extension of the 1H NMR techniques to the investigation of the nephrotoxic potential of other compounds and drugs is discussed.
Mol Pharmacol 1985 Jun
PMID:Proton NMR spectra of urine as indicators of renal damage. Mercury-induced nephrotoxicity in rats. 286 May 59

The metabolic state of human muscle in various functional states has been investigated by the non-invasive technique of 31P nuclear magnetic resonance. The concentrations of phosphocreatine, ATP and inorganic phosphate as well as intracellular pH in the flexor digitorum superficialis have been measured during rest, dynamic exercise and recovery from exercise. The observed relationship between phosphocreatine utilization and decrease in intracellular pH during aerobic exercise indicates that lactate production only becomes significant after more than 60% of the phosphocreatine is used up. Surprisingly intracellular pH may reach as low a value as 5.9 to 6.1, indicating that phosphofructokinase is still partially active at pH 6.0. There is no metabolic recovery if the muscle is made ischaemic following exercise, implying that glycolysis is switched off as soon as exercise is stopped. Lactic acidosis is not the cause of this and presumably Ca2+ is needed to maintain the activation of phosphorylase kinase. The time-course of phosphocreatine recovery after exercise reflects the rate of oxidative metabolism, while pH recovery probably represents H+ ion export from the muscle cell. The dynamics of metabolic changes can now be observed with a time resolution of 10 to 60 seconds and thus disturbances in energy metabolism can be readily detected in several pathological states.
Mol Biol Med 1983 Jul
PMID:Bioenergetics of intact human muscle. A 31P nuclear magnetic resonance study. 667 73

Enzymatic and molecular analyses were conducted on the muscular tissue of a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Significant decreases in activity of complexes I and IV were found and three nucleotide substitutions in the mitochondrial tRNA genes were detected. Two of the substitutions were detected in unaffected members of the family and in some healthy controls. A C-to-T transition mutation at the nucleotide position 3,256 in the mitochondrial tRNA(Leu)(UUR) gene was detected only in the patient and not in unaffected members of the family or 100 healthy controls. The data strongly suggest that this mutation at nucleotide position 3,256 in the mitochondrial tRNA(Leu)(UUR) gene is associated with MELAS.
Biochem Mol Biol Int 1994 Aug
PMID:A mitochondrial tRNA(Leu)(UUR) mutation at 3,256 associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). 780 30

In the last 4 years much progress has been made in the understanding of mitochondrial disorders. Point-mutations, deletions and depletion of the mitochondrial genome are associated with disorders like Leber's disease, MERRF (Myoclonus Epilepsia with Ragged Red Fibers), MELAS (mitochondrial Myopathy, Encephalopathy, Lactic acidosis and Stroke-like episodes) and several others. Recently, mitochondrial dysfunctions have been also related to neurodegenerative disorders like Parkinson's disease and to aging. Since the brain depends mostly on mitochondrial energy supply, mitochondrial dysfunctions may affect the nervous system more severely than other tissues causing or worsening diseases and playing a role in the biological deterioration of aging. Furthermore, the mitochondrial energy supply is associated with the production of highly reactive oxygen species. Ninety-five percent of the molecular oxygen is metabolized within the mitochondria by the electron-transport chain so that mitochondria are highly exposed to oxidative stress which may damage selected neuronal populations. Oxygen radicals created during respiration induce mitochondrial dysfunction which accelerates the production of more deleterious species of oxygen. The latter step further increases mitochondrial malfunction, thus intensifying and perpetuating the cycle. These two mechanisms combined may lead to cell death in brain and other tissues with high metabolic rate. Therefore, in neurodegenerative disorders such as Parkinson's disease mitochondrial dysfunction and oxidative stress may cause or worsen the clinical features.
Biochem Mol Biol Int 1994 Aug
PMID:Oxidative stress and mitochondrial dysfunction in neurodegeneration. 784 18

A single mtDNA point mutation at nt 3243 has been associated with two different clinical phenotypes: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes ('MELAS3243') and progressive external ophthalmoplegia ('PEO3243'). It has been shown that there is a much higher proportion of ragged-red fibers (RRF) with cytochrome c oxidase (COX) deficiency in PEO3243 than in MELAS3243. Using PCR/RFLP analysis of isolated individual skeletal muscle fibers from patients with both syndromes, we found a direct correlation between the localized concentration of the nt 3243 mutation and impairment of COX function at the single muscle fiber level: we found relatively low levels of mutant mtDNAs (56 +/- 21%) in 'normal' fibers; high levels (90 +/- 6%) in COX-positive RRF; and an almost complete segregation of mutant mtDNAs (95 +/- 3%) in COX-negative RRF. Thus, the differential distribution of fibers with extremely high concentrations of mutant mtDNAs characterizes, and probably distinguishes, the skeletal muscle of PEO and MELAS patients harboring the same nt-3243 mutation.
Hum Mol Genet 1994 Mar
PMID:Extremely high levels of mutant mtDNAs co-localize with cytochrome c oxidase-negative ragged-red fibers in patients harboring a point mutation at nt 3243. 791 29

Point mutations in the mitochondrial gene tRNA leucine(UUR) have been associated with maternally inherited mitochondrial myopathies including the MELAS syndrome (Mitochondrial Myopathy Encephalopathy Lactic acidosis and Stroke-like episodes). We describe a further mutation in tRNA leucine(UUR) in a patient with mitochondrial encephalomyopathy, pigmentary retinopathy, dementia, hypoparathyroidism and diabetes mellitus. The mutation was heteroplasmic in the proband's blood (30%) and muscle (76%); it was present at high levels in the proband's affected mother (50% in muscle), and at low levels (< 10%) in blood, muscle and fibroblasts of an unaffected sister. The mutation was not found in 121 normal controls or 35 other patients with mitochondrial disorders. The mutation is at a highly conserved position in the tRNA molecule, close to the 3,243 mutation which is associated with more than 80% of MELAS cases. Further more, both mutations lie within a possible transcriptional control region. This finding adds further support to the evidence that mutations in this region and in other mitochondrial tRNA genes may cause disease.
Hum Mol Genet 1993 Dec
PMID:A new point mutation associated with mitochondrial encephalomyopathy. 811 77

A metabolic investigation was carried out in an eight-month old infant with intrauterine hypotrophia, failure to thrive, psychomotoric retardation and cerebral atrophy, who died after respiratory infections. Blood analysis revealed intermittent lactic acidosis with normal lactate/pyruvate ratio. Activities of cytochrome c oxidase in skeletal muscle, heart, liver and fibroblasts were all in the reference range of controls. Activity of pyruvate dehydrogenase complex (PDH) was decreased in muscle homogenate, heart and liver mitochondria but was normal in cultured skin fibroblasts. Immunodetection of PDH subunits, and assay of El alpha phosphorylation showed in the patient decrease of E1 alpha in skeletal muscle, and enhanced level of E1 alpha phosphorylation in liver mitochondria.
Biochem Mol Biol Int 1993 Dec
PMID:Deficiency of pyruvate dehydrogenase complex in tissues of an eight month old infant. 819

We describe a heteroplasmic 4237-bp mitochondrial DNA (mtDNA) deletion in an 11-year-old girl who has suffered from progressive illness since birth. Her clinical features include global developmental delay with regression, brainstem dysfunction, lactic acidosis, and a history of pancytopenia and failure to thrive. The deletion spanned nt 9498 to nt 13734 and was flanked by a 12-bp direct repeat. Southern blot analysis also revealed an altered ApaI restriction site caused by a G --> A nucleotide substitution at nt 1462 in the 12S rRNA gene. This homoplasmic nucleotide change was presumed to be a mtDNA nucleotide variant. No abnormalities of mitochondrial ultrastructure or distribution were observed, although mild deficiencies were noted for complexes IV, II + III, and I of the mitochondrial respiratory chain. The absence of ragged red fibers and COX-negative fibers in this patient shows that mtDNA deletions do not always result in these classical hallmarks of mitochondrial cytopathies.
Biochem Mol Med 1995 Oct
PMID:mtDNA deletion in a patient with symptoms of mitochondrial cytopathy but without ragged red fibers. 859 34

The expression of several mitochondrial and nuclear genes involved in ATP production was examined in cells cultured from muscle biopsies of patients harboring mitochondrial pathologies. The transcript patterns in muscle cells from the patients affected by carnitine palmitoyl transferase II or 2-ketoglutarate dehydrogenase deficiencies were almost similar to control patterns. In the opposite, patterns were strikingly abnormal in all the other cell cultures from patients with defects in enzymatic complexes involved in oxidative phosphorylation: mitochondrial complex II and III deficiencies, two MELAS syndromes (myopathy, encephalopathy, lactic acidosis and stroke like episodes), a case of Kearns-Sayre syndrome and a case of chronic progressive external ophthalmoplegia. In cultured muscle cells from patients with mtDNA mutations, the percentage of mutated mtDNA was low as compared with those determined in the corresponding skeletal muscle biopsy. Moreover, the complex II defect resulting of a nuclear mutation was not expressed in the cell cultures. Thus, an undetermined transcriptional event, transmitted from muscle biopsies to cultured muscle cells, should be involved to account for such abnormal transcript patterns.
Mol Cell Biochem 1997 Mar
PMID:Expression of oxidative phosphorylation genes in muscle cell cultures from patients with mitochondrial myopathies. 906 96


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