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

Mitochondrial translation is of high significance for cellular energy homeostasis. Aminoacyl-tRNA synthetases (aaRSs) are crucial translational components. Mitochondrial aaRS variants cause various human diseases. However, the pathogenesis of the vast majority of these diseases remains unknown. Here, we identified two novel SARS2 (encoding mitochondrial seryl-tRNA synthetase) variants that cause a multisystem disorder. c.654-14T > A mutation induced mRNA mis-splicing, generating a peptide insertion in the active site; c.1519dupC swapped a critical tRNA-binding motif in the C-terminus due to stop codon readthrough. Both mutants exhibited severely diminished tRNA binding and aminoacylation capacities. A marked reduction in mitochondrial tRNA(Ser)(AGY) was observed due to RNA degradation in patient-derived induced pluripotent stem cells (iPSCs), causing impaired translation and comprehensive mitochondrial function deficiencies. These impairments were efficiently rescued by wild-type SARS2 overexpression. Either mutation caused early embryonic fatality in mice. Heterozygous mice displayed reduced muscle tissue-specific levels of tRNA(Ser)s. Our findings elucidated the biochemical and cellular consequences of impaired translation mediated by SARS2, suggesting that reduced abundance of tRNA(Ser)(AGY) is a key determinant for development of SARS2-related diseases.

Automated summary

Mitochondrial translation is crucial for cellular energy homeostasis, and variations in mitochondrial aaRSs can lead to various human diseases. This study identified two novel variants of SARS2 that cause a multisystem disorder. These variants exhibited reduced tRNA binding and aminoacylation capacities, resulting in mitochondrial dysfunction and decreased tRNA abundance due to RNA degradation. The findings highlight the importance of reduced tRNA(Ser)(AGY) abundance in the development of SARS2-related diseases.