Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0162671 (MELAS)
 587 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two novel modified uridines were identified from mammalian mitochondrial (mt) tRNAs. Mass spectrometric analysis revealed that they are modified uridines possessing a sulfonic acid group derived from taurine; 5-taurinomethyl-uridine from mt tRNAs for Trp and Leu(UUR), and 5-taurinomethyl-2-thiouridine from mt tRNAs for Lys, Gln and Glu. We have found lack of modification of these taurine-containing uridines in mutant mt tRNAs for Leu(UUR) and Lys from pathogenic cells of mitochondrial encephalomyopathies, MELAS and MERRF, respectively.
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PMID:Novel taurine-containing uridine derivatives and mitochondrial human diseases. 1283 62

Point mutations in mitochondrial (mt) tRNA genes are associated with a variety of human mitochondrial diseases. We have shown previously that mt tRNA(Leu(UUR)) with a MELAS A3243G mutation and mt tRNA(Lys) with a MERRF A8344G mutation derived from HeLa background cybrid cells are deficient in normal taurine-containing modifications [taum(5)(s(2))U; 5-taurinomethyl-(2-thio)uridine] at the anticodon wobble position in both cases. The wobble modification deficiency results in defective translation. We report here wobble modification deficiencies of mutant mt tRNAs from cybrid cells with different nuclear backgrounds, as well as from patient tissues. These findings demonstrate the generality of the wobble modification deficiency in mutant tRNAs in MELAS and MERRF.
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PMID:Wobble modification deficiency in mutant tRNAs in patients with mitochondrial diseases. 1589 15

By purifying mutant mitochondrial tRNAs, we were able to ascertain that post-transcriptional modification at the anticodon wobble uridine is absent in tRNA(Lys) with the 8344 MERRF mutation and in tRNA(Leu(UUR)) with either the 3243 or 3271 MELAS mutation. Both the MERRF and MELAS mutant tRNAs substantially lost their translational ability, the extent of the loss in each mutant corresponding to the reduction in actual mitochondrial translational activity. Lack of the wobble modification deprived mutant tRNA(Lys) of interaction with the cognate codons. These features indicate that the modification defect plays a primary role in the molecular pathophysiology of these mitochondrial diseases.
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PMID:Wobble modification defect suppresses translational activity of tRNAs with MERRF and MELAS mutations. 1612 Mar 15

The A3243G mutation in the mitochondrial gene for human mitochondrial (mt) tRNA(Leu(UUR)), responsible for decoding of UUR codons, is associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). We previously demonstrated that this mutation causes defects in 5-taurinomethyluridine (taum(5)U) modification at the anticodon first (wobble) position of the mutant mt tRNA(Leu(UUR)), leading to a UUG decoding deficiency and entraining severe respiratory defects. In addition, we previously identified a heteroplasmic mutation, G12300A, in the other mt leucine tRNA gene, mt tRNA(Leu(CUN)), which functions as a suppressor of the A3243G respiratory defect in cybrid cells containing A3243G mutant mtDNA. Although the G12300A mutation converts the anticodon sequence of mt tRNA(Leu(CUN)) from UAG to UAA, this tRNA carrying an unmodified wobble uridine still cannot decode the UUG codon. Mass spectrometric analysis of the suppressor mt tRNA(Leu(CUN)) carrying the G12300A mutation from the phenotypically revertant cells revealed that the wobble uridine acquires de novo taum(5)U modification. In vitro translation confirmed the functionality of the suppressor tRNA for decoding UUG codons. These results demonstrate that the acquisition of the wobble modification in another isoacceptor tRNA is critical for suppressing the MELAS mutation, and they highlight the primary role of the UUG decoding deficiency in the molecular pathogenesis of MELAS syndrome.
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PMID:Acquisition of the wobble modification in mitochondrial tRNALeu(CUN) bearing the G12300A mutation suppresses the MELAS molecular defect. 1644 7

A growing number of mutations in mitochondrial (mt) tRNA genes have been found to associate with human mitochondrial diseases. Our previous analysis of mutant mt tRNAs isolated from cells derived from patients with mitochondrial diseases revealed the lack of a post-transcriptional taurine-modification at the anticodon wobble uridine in two mt tRNAs bearing typical pathogenic mutations: mt tRNA(Leu(UUR)) with either the MELAS 3243 or 3271 mutation and mt tRNA(Lys) with the MERRF 8344 mutation. We here summarize our recent studies that clarify the molecular basis of the defective mitochondrial translation caused by this wobble modification deficiency. The MERRF mt tRNA(Lys) lacking the wobble modification cannot translate either of its codons (AAA and AAG), while the translational activity of MELAS mt tRNA(Leu(UUR)) lacking wobble modification is more depressed in decoding of UUG codon than UUA codon. These findings suggest that the wobble modification deficiency plays a primary role in the molecular pathogenesis of the MELAS and MERRF mitochondrial diseases.
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PMID:Human mitochondrial diseases associated with tRNA wobble modification deficiency. 1713 41

Mitochondrial DNA mutations that cause mitochondrial dysfunction are responsible for a wide spectrum of human diseases, referred to as mitochondrial diseases. Pathogenic point mutations are found frequently in genes encoding mitochondrial (mt) tRNAs, indicating that impaired functioning of mutant mt tRNAs is the primary cause of mitochondrial dysfunction. Our previous studies revealed the absence of posttranscriptional taurine modification at the anticodon wobble uridine in mutant mt tRNAs isolated from cells derived from patients with two major classes of mitochondrial diseases, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonus epilepsy associated with ragged red fibers). Defective taurine modification of the mutant mt tRNAs results in a deficiency in protein synthesis as the cognate codons of the mutant mt tRNA cannot be decoded. These findings represent the first evidence of a molecular pathogenesis caused by an RNA modification disorder.
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PMID:Human mitochondrial diseases caused by lack of taurine modification in mitochondrial tRNAs. 2195 23

Mitochondrial dysfunction activates mitochondria-to-nucleus signaling pathways whose components are mostly unknown. Identification of these components is important to understand the molecular mechanisms underlying mitochondrial diseases and to discover putative therapeutic targets. MELAS syndrome is a rare neurodegenerative disease caused by mutations in mitochondrial (mt) DNA affecting mt-tRNA(Leu(UUR)). Patient and cybrid cells exhibit elevated oxidative stress. Moreover, mutant mt-tRNAs(Leu(UUR)) lack the taurine-containing modification normally present at the wobble uridine (U34) of wild-type mt-tRNA(Leu(UUR)), which is considered an etiology of MELAS. However, the molecular mechanism is still unclear. We found that MELAS cybrids exhibit a significant decrease in the steady-state levels of several mt-tRNA-modification enzymes, which is not due to transcriptional regulation. We demonstrated that oxidative stress mediates an NFkB-dependent induction of microRNA-9/9*, which acts as a post-transcriptional negative regulator of the mt-tRNA-modification enzymes GTPBP3, MTO1 and TRMU. Down-regulation of these enzymes by microRNA-9/9* affects the U34 modification status of non-mutant tRNAs and contributes to the MELAS phenotype. Anti-microRNA-9 treatments of MELAS cybrids reverse the phenotype, whereas miR-9 transfection of wild-type cells mimics the effects of siRNA-mediated down-regulation of GTPBP3, MTO1 and TRMU. Our data represent the first evidence that an mt-DNA disease can directly affect microRNA expression. Moreover, we demonstrate that the modification status of mt-tRNAs is dynamic and that cells respond to stress by modulating the expression of mt-tRNA-modifying enzymes. microRNA-9/9* is a crucial player in mitochondria-to-nucleus signaling as it regulates expression of nuclear genes in response to changes in the functional state of mitochondria.
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PMID:The ROS-sensitive microRNA-9/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome. 2514 73