Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease.

@article{Kirino2004CodonspecificTD,
  title={Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease.},
  author={Yohei Kirino and Takehiro Yasukawa and Shigeo Ohta and Shigeo Akira and Kaisuke Ishihara and Kimitsuna Watanabe and Tsutomu Suzuki},
  journal={Proceedings of the National Academy of Sciences of the United States of America},
  year={2004},
  volume={101 42},
  pages={
          15070-5
        }
}
Point mutations in the mitochondrial (mt) tRNA(Leu(UUR)) gene are responsible for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a subgroup of mitochondrial encephalomyopathic diseases. We previously showed that mt tRNA(Leu(UUR)) with an A3243G or T3271C mutation derived from patients with MELAS are deficient in a normal taurine-containing modification (taum5U; 5-taurinomethyluridine) at the anticodon wobble position. To examine decoding disorder of… Expand
Human Mitochondrial Diseases Associated with tRNA Wobble Modification Deficiency
TLDR
Findings suggest that the wobble modification deficiency plays a primary role in the molecular pathogenesis of the MELAS and MERRF mitochondrial diseases. Expand
Acquisition of the wobble modification in mitochondrial tRNALeu(CUN) bearing the G12300A mutation suppresses the MELAS molecular defect.
TLDR
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 M ELAS syndrome. Expand
Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease.
TLDR
It is reported here that mitochondrial tRNAs harboring one of five mutations found in tissues from patients with symptoms of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) lacked the normal taurine-containing modification at the anticodon wobble position, which strongly suggest deficient wobble modification could be a key molecular factor responsible for the phenotypic features of MELAS. Expand
The A3243G tRNALeu(UUR) mutation induces mitochondrial dysfunction and variable disease expression without dominant negative acting translational defects in complex IV subunits at UUR codons.
TLDR
It is shown that the mtDNA-encoded cytochrome c oxidase I (COX I) and COX II exist exclusively with the correct amino acid sequences in A3243G cells in a misassembled complex IV, leaving tissue-specific accumulation by mtDNA segregation as the most likely cause of variable mitochondrial disease expression. Expand
Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria
TLDR
It is demonstrated that nuclear expression and mitochondrial targeting of specifically designed transgenic tRNAs results in an improvement of mitochondrial translation, increased levels of mitochondrial DNA-encoded respiratory complexes subunits, and significant rescue of respiration. Expand
Wobble modification deficiency in mutant tRNAs in patients with mitochondrial diseases
TLDR
Wobble modification deficiencies of mutant mt tRNAs from cybrid cells with different nuclear backgrounds, as well as from patient tissues, demonstrate the generality of the wobble modification deficiency in mutant t RNAs in MELAS and MERRF. Expand
Human Mitochondrial Leucyl-tRNA Synthetase Corrects Mitochondrial Dysfunctions Due to the tRNALeu(UUR) A3243G Mutation, Associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Symptoms and Diabetes
TLDR
It is demonstrated that the transfer of human mitochondrial leucyl-tRNA synthetase into the cybrid cells carrying the A3243G mutation improved the efficiency of aminoacylation and stability of mitochondrial tRNAs and then increased the rates of mitochondrial translation and respiration, consequently correcting the mitochondrial dysfunction. Expand
The A 3243 G tRNALeu ( UUR ) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG 2
The majority of patients with MELAS (mitochondrial encephalomyophathy, lactic acidosis, stroke-like episodes) carry a heteroplasmic A3243G mutation in the mitochondrial tRNA. The mutation preventsExpand
The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2.
TLDR
Data demonstrate that the A3243G mutation produces both loss- and gain-of-function phenotypes, explaining the apparent discrepancy between the severity of the translation and respiratory chain assembly defects, and suggest a function for EFG2 in quality control of translation elongation. Expand
A Disease-causing Point Mutation in Human Mitochondrial tRNAMet Results in tRNA Misfolding Leading to Defects in Translational Initiation and Elongation*
TLDR
It is shown that the single 8U→C mutation leads to a failure of the tRNA to respond conformationally to Mg2+. Expand
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TLDR
Both of the mutant tRNA molecules were deficient in a modification of uridine that occurs in the normal tRNALeu(UUR) at the first position of the anticodon, which may lead to the mistranslation of leucine into non-cognate phenylalanine codons by mutant tRNAsLeu(U UR), according to the mitochondrial wobble rule, and a decrease in the rate of mitochondrial protein synthesis. Expand
Wobble modification defect in tRNA disturbs codon–anticodon interaction in a mitochondrial disease
TLDR
It is concluded that the anticodon base modification defect, which is forced by the pathogenic point mutation, disturbs codon–anticodon pairing in the mutant tRNALys, leading to a severe reduction in mitochondrial translation that eventually could result in the onset of MERRF. Expand
Defect in modification at the anticodon wobble nucleotide of mitochondrial tRNALys with the MERRF encephalomyopathy pathogenic mutation
TLDR
It is suggested that normally modified uridine at the anticodon wobble position remains unmodified in the purified mutant tRNALys, and is responsible for the pathogenesis of mitochondrial diseases. Expand
The Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episode Syndrome-associated Human Mitochondrial tRNALeu(UUR) Mutation Causes Aminoacylation Deficiency and Concomitant Reduced Association of mRNA with Ribosomes*
TLDR
Several lines of evidence indicate that the protein synthesis defect in A3243G MELAS mutation-carrying cells is mainly due to a reduced association of mRNA with ribosomes, possibly as a consequence of the tRNALeu(UUR)aminoacylation defect. Expand
The pathogenic U3271C human mitochondrial tRNA(Leu(UUR)) mutation disrupts a fragile anticodon stem.
The U3271C mutation affecting the human mitochondrial transfer RNA(Leu(UUR)) (hs mt tRNA) is correlated with diabetes and mitochondrial encephalopathies. We have explored the relationship between theExpand
Impairment of mitochondrial transcription termination by a point mutation associated with the MELAS subgroup of mitochondrial encephalomyopathies
TLDR
It is found that the MELAS mutation results in severe impairment of 16S rRNA transcription termination, which correlates with a reduced affinity of the partially purified termination protein for the M ELAS template, which suggests that the molecular defect in MELAs is the inability to produce the correct type and quantity of rRNA relative to other mitochondrial gene products. Expand
Respiration-deficient cells are caused by a single point mutation in the mitochondrial tRNA-Leu (UUR) gene in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS).
TLDR
The single point mutation causes the functional abnormality in the respiratory chain of mitochondria in MELAS, a major subgroup of heterogeneous mitochondrial diseases. Expand
A point mutation in the mitochondrial tRNA(Leu)(UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes).
TLDR
This work suggests that the mutation in the mitochondrial tRNALeu gene causes MELAS, a major group of heterogeneous mitochondrial disorders. Expand
Accumulation of mtDNA with a mutation at position 3271 in tRNA(Leu)(UUR) gene introduced from a MELAS patient to HeLa cells lacking mtDNA results in progressive inhibition of mitochondrial respiratory function.
TLDR
A new mitochondrial DNA mutation of tRNA(Leu)(UUR) at nucleotide position 3271 (MELAS3271) was determined to be involved in the pathogenic process of mitochondrial diseases MELAS using intercellular transfer of patient-derived mtDNA to mtDNA-less HeLa cells. Expand
MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts.
The pathogenetic mechanism of the mitochondrial tRNA(LeuUUR) gene mutation responsible for the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome wasExpand
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