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.

@article{Sasarman2008TheAT,
  title={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.},
  author={Florin Sasarman and Hana Antonicka and Eric A. Shoubridge},
  journal={Human molecular genetics},
  year={2008},
  volume={17 23},
  pages={
          3697-707
        }
}
The majority of patients with MELAS (mitochondrial encephalomyophathy, lactic acidosis, stroke-like episodes) carry a heteroplasmic A3243G mutation in the mitochondrial tRNA(Leu(UUR)). The mutation prevents modification of the wobble U base, impairing translation at UUA and UUG codons; however, whether this results in amino acid misincorporation in the mitochondrial translation products remains controversial. We tested this hypothesis in homoplasmic mutant myoblasts isolated from a MELAS… 
View on PubMed
doi.org
129 Citations
Highly Influential Citations
4
Background Citations
62
Methods Citations
5
Results Citations
2

Figures and Tables from this paper

129 Citations

Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease

These findings elucidated the biochemical and cellular consequences of impaired translation mediated by SARS2, suggesting that reduced abundance of tRNASer(AGY) is a key determinant for development of Sars2-related diseases.

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

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.

Exploring the Ability of LARS2 Carboxy-Terminal Domain in Rescuing the MELAS Phenotype

It is found that Cterm ameliorates de novo mitochondrial protein synthesis, whilst it has no effect on mt-tRNALeu(UUR) steady-state levels and aminoacylation, which suggest that the beneficial effect of Cterm may be mediated by factors that are independent of the mitochondrial bioenergetics.

Overexpression of mitochondrial histidyl-tRNA synthetase restores mitochondrial dysfunction caused by a deafness-associated tRNAHis mutation

Results indicate that HARS2 overexpression corrects the mitochondrial dysfunction caused by the tRNAHis mutation and provide critical insights into the pathophysiology of mitochondrial disease and represent a step toward improved therapeutic interventions for mitochondrial disorders.

Defects in mitochondrial RNA metabolism in disease

This work confirmed previously identified RNA processing defects, identified common internal cleavage sites and new sites unique to the m.3243A>G mutants that do not correspond to transcript ends, and identified regions of importance to the processing of mtRNAs.

Defects in RNA metabolism in mitochondrial disease.

Functional consequences of mitochondrial tRNATrp and tRNAArg mutations causing combined OXPHOS defects

The results show that these tRNATrp and tRNAArg mutations cause the combined OXPHOS deficiencies in the patients, adding to the still expanding group of pathogenic mitochondrial tRNA mutations.

The phenotypic expression of mitochondrial tRNA-mutations can be modulated by either mitochondrial leucyl-tRNA synthetase or the C-terminal domain thereof

It is shown that the isolated carboxy-terminal domain of human mt-leucyl tRNA synthetase (LeuRS-Cterm) localizes to mitochondria and ameliorates the energetic defect in transmitochondrial cybrids carrying mutations either in the cognate mt-tRNALeu(UUR) or in the non-cognatemt-tRNAIle gene.

MELAS Syndrome: Mediated by Impaired Taurinomethyluridine Synthesis

The taurine-deficient model has aided in the identification of at least one pathological pathway that contributes to the development of the MELAS disorder.

Exposure to arginine analog canavanine induces aberrant mitochondrial translation products, mitoribosome stalling, and instability of the mitochondrial proteome.

...

References

SHOWING 1-10 OF 56 REFERENCES

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.

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.

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

It is concluded that the UUG codon-specific translational defect of the mutant mt tRNAs(Leu(UUR)) is the primary cause of MELAS at the molecular level.

Modification Defect at Anticodon Wobble Nucleotide of Mitochondrial tRNAsLeu(UUR) with Pathogenic Mutations of Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes*

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.

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.

Results provide evidence for a direct relationship between the tRNALeu(UUR) mutation and the pathogenesis of this mitochondrial disease.

The 7472insC Mitochondrial DNA Mutation Impairs the Synthesis and Extent of Aminoacylation of tRNASer(UCN) but Not Its Structure or Rate of Turnover*

It is inferred that the 7472insC mitochondrial DNA mutation acts posttranscriptionally to decrease tRNASer(UCN) abundance by affecting its synthesis rather than its stability, indicating a common molecular process underlying sensorineural deafness caused by mitochondrial tR NASer( UCN) mutations.

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*

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.

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 was…

The Diabetes-associated 3243 Mutation in the Mitochondrial tRNALeu(UUR) Gene Causes Severe Mitochondrial Dysfunction without a Strong Decrease in Protein Synthesis Rate*

The results favor a scheme in which the 3243 mutation causes loss of respiration through accelerated protein degradation, leading to a disequilibrium between the levels of mitochondrial and nuclear encoded respiratory chain subunits and thereby a reduction of functional respiratory chain complexes.

Oxidative phosphorylation defect in the brains of carriers of the tRNAleu(UUR) A3243G mutation in a MELAS pedigree

It is found that brain lactate, a sensitive indicator of oxidative phosphorylation dysfunction, was linearly related to the proportion of mutant mtDNAs in all individuals carrying the A3243G mutation, whether they were symptomatic or not.

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.

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.
...