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

Fan, Wenlu; Zheng, Jing; Kong, Wanzhong; Cui, Limei; Aishanjiang, Maerhaba; Yi, Qiuzi; Wang, Min; Cang, Xiaohui; Tang, Xiaowen; Chen, Ye; Mo, Jun Qin; Sondheimer, Neal; Ge, Wanzhong; Guan, Min‐Xin

doi:10.1074/jbc.ra119.010598

Cited by 20 publications

(11 citation statements)

References 67 publications

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“…22,49,50 The reduced levels among the 13 mtDNA-encoding OXPHOS subunits in the cells bearing the YARS2 mutations were correlated with the tyrosine codon usage of polypeptides, with especially pronounced effects in the subunits with higher tyrosine codon content such as ND1, ND4, ND5, ND6, CO1, and CO2. 22,49,[51][52][53] In the present study, more drastic reductions in the level of ND1 were observed in the cell lines bearing both m.3635G>A and homozygous YARS2 p.191Gly>Val mutations than in cells harboring both m.3635G>A and heterozygous YARS2 p.191Gly>Val or only the m.3635G>A mutation. Notably, the levels of CO2 in these mutant cell lines bearing both m.3635G>A and homozygous YARS2 p.191Gly>Val mutations, both m.3635G>A and heterozygous YARS2 p.191Gly>Val mutations, or only the m.3635G>A mutation were 102%, 97%, and 70%, respectively, of those in the control cell line.…”

Section: Discussionsupporting

confidence: 53%

Leber's Hereditary Optic Neuropathy Arising From the Synergy Between ND1 3635G>A Mutation and Mitochondrial YARS2 Mutations

Jin

Zhang

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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To investigate the mechanism underlying the synergic interaction between Leber's hereditary optic neuropathy (LHON)-associated ND1 and mitochondrial tyrosyl-tRNA synthetase (YARS2) mutations. METHODS.Molecular dynamics simulation and differential scanning fluorimetry were used to evaluate the structure and stability of proteins. The impact of ND1 3635G>A and YARS2 p.G191V mutations on the oxidative phosphorylation machinery was evaluated using blue native gel electrophoresis and enzymatic activities assays. Assessment of reactive oxygen species (ROS) production in cell lines was performed by flow cytometry with MitoSOX Red reagent. Analysis of effect of mutations on autophagy was undertaken via flow cytometry for autophagic flux. RESULTS.Members of one Chinese family bearing both the YARS2 p.191Gly>Val and m.3635G>A mutations exhibited much higher penetrance of optic neuropathy than those pedigrees carrying only the m.3635G>A mutation. The m.3635G>A (p.Ser110Asn) mutation altered the ND1 structure and function, whereas the p.191Gly>Val mutation affected the stability of YARS2. Lymphoblastoid cell lines harboring both m.3635G>A and p.191Gly>Val mutations revealed more reductions in the levels of mitochondrionencoding ND1 and CO2 than cells bearing only the m.3635G>A mutation. Strikingly, both m.3635G>A and p.191Gly>Val mutations exhibited decreases in the nucleus-encoding subunits of complex I and IV. These deficiencies manifested greater defects in the stability and activities of complex I and complex IV and overproduction of ROS and promoted greater autophagy in cell lines harboring both m.3635G>A and p.191Gly>Val mutations compared with cells bearing only the m.3635G>A mutation. CONCLUSIONS.Our findings provide new insights into the pathophysiology of LHON arising from the synergy between ND1 3635G>A mutation and mitochondrial YARS2 mutations.

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Section: Discussionsupporting

confidence: 53%

Leber's Hereditary Optic Neuropathy Arising From the Synergy Between ND1 3635G>A Mutation and Mitochondrial YARS2 Mutations

Jin

Zhang

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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“…As a result, the pleiotropic effects of m.4295A>G mutation on tRNA Ile metabolism including the processing of tRNA precursors, stability and aminoacylation of tRNA Ile contributed to marked reductions in the steady-state level of tRNA Ile , in contrast with mild reductions in tRNA Asp and tRNA Met observed in the cell lines bearing the m.7551A>G and m.4435A>G mutations ( 31 , 32 ). Notably, the reduced levels of tRNA Ile in mutant cells harboring the m.4295A>G mutation approached the proposed threshold level, which is 30% of the control levels of tRNA, to support the normal rate of mitochondrial translation ( 62 , 79–81 ).…”

Section: Discussionmentioning

confidence: 84%

A deafness-associated tRNA mutation caused pleiotropic effects on the m1G37 modification, processing, stability and aminoacylation of tRNAIle and mitochondrial translation

Meng

Zhou

Xiao

et al. 2021

Nucleic Acids Research

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Defects in the posttranscriptional modifications of mitochondrial tRNAs have been linked to human diseases, but their pathophysiology remains elusive. In this report, we investigated the molecular mechanism underlying a deafness-associated tRNAIle 4295A>G mutation affecting a highly conserved adenosine at position 37, 3′ adjacent to the tRNA’s anticodon. Primer extension and methylation activity assays revealed that the m.4295A>G mutation introduced a tRNA methyltransferase 5 (TRMT5)-catalyzed m1G37 modification of tRNAIle. Molecular dynamics simulations suggested that the m.4295A>G mutation affected tRNAIle structure and function, supported by increased melting temperature, conformational changes and instability of mutated tRNA. An in vitro processing experiment revealed that the m.4295A>G mutation reduced the 5′ end processing efficiency of tRNAIle precursors, catalyzed by RNase P. We demonstrated that cybrid cell lines carrying the m.4295A>G mutation exhibited significant alterations in aminoacylation and steady-state levels of tRNAIle. The aberrant tRNA metabolism resulted in the impairment of mitochondrial translation, respiratory deficiency, decreasing membrane potentials and ATP production, increasing production of reactive oxygen species and promoting autophagy. These demonstrated the pleiotropic effects of m.4295A>G mutation on tRNAIle and mitochondrial functions. Our findings highlighted the essential role of deficient posttranscriptional modifications in the structure and function of tRNA and their pathogenic consequence of deafness.

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“…The phenotypic expression of variants in mitochondrial DNA could be modulated by nuclear modifier genes, which may also play an important role in inherited hearing loss. Fan et al had found that the interaction between p.191Gly>-Val mutation in mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) and the 7511A>G mutation in tRNA Ser(UCN) caused hearing loss [102]. Moreover, in the study of Chinese families, people who suffer both mutations present much higher penetrance of hearing loss than those who carry only one [102].…”

Section: Inherited Hearing Lossmentioning

confidence: 99%

“…Fan et al had found that the interaction between p.191Gly>-Val mutation in mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) and the 7511A>G mutation in tRNA Ser(UCN) caused hearing loss [102]. Moreover, in the study of Chinese families, people who suffer both mutations present much higher penetrance of hearing loss than those who carry only one [102]. Mtu1 is a tRNA-modifying enzyme and mtu1 knockout zebrafish exhibited a smaller number of hair cells and reductions in the hair bundle densities in the auditory and vestibular organs [103].…”

Section: Inherited Hearing Lossmentioning

confidence: 99%

Mitochondrial Dysfunction and Sirtuins: Important Targets in Hearing Loss

Zhang

Gong

2021

Neural Plasticity

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Mitochondrial dysfunction has been suggested to be a risk factor for sensorineural hearing loss (SNHL) induced by aging, noise, ototoxic drugs, and gene. Reactive oxygen species (ROS) are mainly derived from mitochondria, and oxidative stress induced by ROS contributes to cochlear damage as well as mitochondrial DNA mutations, which may enhance the sensitivity and severity of hearing loss and disrupt ion homeostasis (e.g., Ca2+ homeostasis). The formation and accumulation of ROS further undermine mitochondrial components and ultimately lead to apoptosis and necrosis. SIRT3–5, located in mitochondria, belong to the family of sirtuins, which are highly conserved deacetylases dependent on nicotinamide adenine dinucleotide (NAD+). These deacetylases regulate diverse cellular biochemical activities. Recent studies have revealed that mitochondrial sirtuins, especially SIRT3, modulate ROS levels in hearing loss pathologies. Although the precise functions of SIRT4 and SIRT5 in the cochlea remain unclear, the molecular mechanisms in other tissues indicate a potential protective effect against hearing loss. In this review, we summarize the current knowledge regarding the role of mitochondrial dysfunction in hearing loss, discuss possible functional links between mitochondrial sirtuins and SNHL, and propose a perspective that SIRT3–5 have a positive effect on SNHL.

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

Cited by 20 publications

References 67 publications

Leber's Hereditary Optic Neuropathy Arising From the Synergy Between ND1 3635G>A Mutation and Mitochondrial YARS2 Mutations

Leber's Hereditary Optic Neuropathy Arising From the Synergy Between ND1 3635G>A Mutation and Mitochondrial YARS2 Mutations

A deafness-associated tRNA mutation caused pleiotropic effects on the m1G37 modification, processing, stability and aminoacylation of tRNAIle and mitochondrial translation

Mitochondrial Dysfunction and Sirtuins: Important Targets in Hearing Loss

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

Cited by 20 publications

References 67 publications

Leber's Hereditary Optic Neuropathy Arising From the Synergy Between ND1 3635G&gt;A Mutation and Mitochondrial YARS2 Mutations

Leber's Hereditary Optic Neuropathy Arising From the Synergy Between ND1 3635G&gt;A Mutation and Mitochondrial YARS2 Mutations

A deafness-associated tRNA mutation caused pleiotropic effects on the m1G37 modification, processing, stability and aminoacylation of tRNAIle and mitochondrial translation

Mitochondrial Dysfunction and Sirtuins: Important Targets in Hearing Loss

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Product

Resources

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Leber's Hereditary Optic Neuropathy Arising From the Synergy Between ND1 3635G>A Mutation and Mitochondrial YARS2 Mutations

Leber's Hereditary Optic Neuropathy Arising From the Synergy Between ND1 3635G>A Mutation and Mitochondrial YARS2 Mutations