Dataset Information

Contribution of a mitochondrial tyrosyl-tRNA synthetase mutation to the phenotypic expression of the deafness-associated tRNA^Ser(UCN) 7511A>G mutation.

ABSTRACT: Nuclear modifier genes have been proposed to modify the phenotypic expression of mitochondrial DNA mutations. Using a targeted exome-sequencing approach, here we found that the p.191Gly>Val mutation in mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) interacts with the tRNA^Ser(UCN) 7511A>G mutation in causing deafness. Strikingly, members of a Chinese family bearing both the YARS2 p.191Gly>Val and m.7511A>G mutations displayed much higher penetrance of deafness than those pedigrees carrying only the m.7511A>G mutation. The m.7511A>G mutation changed the A4:U69 base-pairing to G4:U69 pairing at the aminoacyl acceptor stem of tRNA^Ser(UCN) and perturbed tRNA^Ser(UCN) structure and function, including an increased melting temperature, altered conformation, instability, and aberrant aminoacylation of mutant tRNA. Using lymphoblastoid cell lines derived from symptomatic and asymptomatic members of these Chinese families and control subjects, we show that cell lines harboring only the m.7511A>G or p.191Gly>Val mutation revealed relatively mild defects in tRNA^Ser(UCN) or tRNA^Tyr metabolism, respectively. However, cell lines harboring both m.7511A>G and p.191Gly>Val mutations displayed more severe defective aminoacylations and lower tRNA^Ser(UCN) and tRNA^Tyr levels, aberrant aminoacylation, and lower levels of other tRNAs, including tRNA^Thr, tRNA^Lys, tRNA^Leu(UUR), and tRNA^Ser(AGY), than those in the cell lines carrying only the m.7511A>G or p.191Gly>Val mutation. Furthermore, mutant cell lines harboring both m.7511A>G and p.191Gly>Val mutations exhibited greater decreases in the levels of mitochondrial translation, respiration, and mitochondrial ATP and membrane potentials, along with increased production of reactive oxygen species. Our findings provide molecular-level insights into the pathophysiology of maternally transmitted deafness arising from the synergy between tRNA^Ser(UCN) and mitochondrial YARS mutations.

SUBMITTER: Fan W

PROVIDER: S-EPMC6916496 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Contribution of a mitochondrial tyrosyl-tRNA synthetase mutation to the phenotypic expression of the deafness-associated tRNA<sup>Ser(UCN)</sup> 7511A>G mutation.

Fan Wenlu W Zheng Jing J Kong Wanzhong W Cui Limei L Aishanjiang Maerhaba M Yi Qiuzi Q Wang Min M Cang Xiaohui X Tang Xiaowen X Chen Ye Y Mo Jun Qin JQ Sondheimer Neal N Ge Wanzhong W Guan Min-Xin MX

The Journal of biological chemistry 20191104 50

Nuclear modifier genes have been proposed to modify the phenotypic expression of mitochondrial DNA mutations. Using a targeted exome-sequencing approach, here we found that the p.191Gly>Val mutation in mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) interacts with the tRNA<sup>Ser(UCN)</sup> 7511A>G mutation in causing deafness. Strikingly, members of a Chinese family bearing both the YARS2 p.191Gly>Val and m.7511A>G mutations displayed much higher penetrance of deafness than those pedigrees car ...[more]

PMID: 31685661

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Project description:The deafness-associated m.12201T>C mutation affects the A5-U68 base-pairing within the acceptor stem of mitochondrial tRNAHis The primary defect in this mutation is an alteration in tRNAHis aminoacylation. Here, we further investigate the molecular mechanism of the deafness-associated tRNAHis 12201T>C mutation and test whether the overexpression of the human mitochondrial histidyl-tRNA synthetase gene (HARS2) in cytoplasmic hybrid (cybrid) cells carrying the m.12201T>C mutation reverses mitochondrial dysfunctions. Using molecular dynamics simulations, we demonstrate that the m.12201T>C mutation perturbs the tRNAHis structure and function, supported by decreased melting temperature, conformational changes, and instability of mutated tRNA. We show that the m.12201T>C mutation-induced alteration of aminoacylation tRNAHis causes mitochondrial translational defects and respiratory deficiency. We found that the transfer of HARS2 into the cybrids carrying the m.12201T>C mutation raises the levels of aminoacylated tRNAHis from 56.3 to 75.0% but does not change the aminoacylation of other tRNAs. Strikingly, HARS2 overexpression increased the steady-state levels of tRNAHis and of noncognate tRNAs, including tRNAAla, tRNAGln, tRNAGlu, tRNALeu(UUR), tRNALys, and tRNAMet, in cells bearing the m.12201T>C mutation. This improved tRNA metabolism elevated the efficiency of mitochondrial translation, activities of oxidative phosphorylation complexes, and respiration capacity. Furthermore, HARS2 overexpression markedly increased mitochondrial ATP levels and membrane potential and reduced production of reactive oxygen species in cells carrying the m.12201T>C mutation. These results indicate that HARS2 overexpression corrects the mitochondrial dysfunction caused by the tRNAHis mutation. These findings provide critical insights into the pathophysiology of mitochondrial disease and represent a step toward improved therapeutic interventions for mitochondrial disorders.

Dataset Information

Contribution of a mitochondrial tyrosyl-tRNA synthetase mutation to the phenotypic expression of the deafness-associated tRNA^Ser(UCN) 7511A>G mutation.

Publications

Contribution of a mitochondrial tyrosyl-tRNA synthetase mutation to the phenotypic expression of the deafness-associated tRNA<sup>Ser(UCN)</sup> 7511A>G mutation.

Similar Datasets

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Dataset Information

Contribution of a mitochondrial tyrosyl-tRNA synthetase mutation to the phenotypic expression of the deafness-associated tRNASer(UCN) 7511A>G mutation.

Publications

Contribution of a mitochondrial tyrosyl-tRNA synthetase mutation to the phenotypic expression of the deafness-associated tRNA<sup>Ser(UCN)</sup> 7511A>G mutation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Contribution of a mitochondrial tyrosyl-tRNA synthetase mutation to the phenotypic expression of the deafness-associated tRNA^Ser(UCN) 7511A>G mutation.