| Summary: | <p>Mitochondrial aminoacyl-tRNA synthetases (mtRS) are vital for mitochondrial translation. mtRSs catalyse the aminoacylation of mitochondrial tRNA with their cognate amino acid. Mutations in mtRS genes are associated with distinct clinical pathologies in humans. Studying mtRS mutations in model organisms is difficult because mtRS knock-out alleles are haplosufficient and cause embryonic lethality in their homozygous state. In this study, we phenotypically and mechanistically characterised a hypomorphic, ENU-induced <em>Wars2</em> allele (<em>Wars2</em>-V117L) in mouse with the aim to determine the cause of the tissue-specific penetrance of mtRS mutant alleles.</p> <p>The <em>Wars2</em>-V117L allele caused tissue-specific pathology in mice. <em>Wars2<sup>V117L/V117L</sup></em> mice developed hypertrophic cardiomyopathy, sensorineural hearing loss, reduced adiposity, increased glucose tolerance and systemic changes in metabolism. Furthermore, we showed that the <em>Wars2<sup>V117L/V117L</sup></em> allele causes abnormal adipose tissue pathology as shown by 'browning' of WAT depots and lipid accumulation in BAT in <em>Wars2<sup>V117L/V117L</sup></em>mice.</p> <p>The <em>Wars2</em>V117L/V117L allele disrupts <em>Wars2</em> mRNA splicing, resulting in reduced full-length <em>Wars2</em> (Wars2-FL) mRNA in <em>Wars2<sup>V117L/V117L</sup></em> tissues and cells. Reduced Wars2-FL mRNA caused tissue-specific reductions in mt-TrpRS protein and mitochondrial OXPHOS deficiencies in <em>Wars2<sup>V117L/V117L</sup></em> mice <em>in vivo</em>. OXPHOS deficiencies lead to activation of the Integrated Stress Response (ISR) in <em>Wars2<sup>V117L/V117L</sup></em> heart and liver. Activation of the ISR in Wars2V117L/V117L heart caused up-regulation of Fgf21 mRNA and increased plasma FGF21, leading to systemic changes in metabolism. Finally, we showed that up-regulation of <em>Pgc1a</em> and mitochondrial biogenesis prevented inhibition of mitochondrial translation in <em>Wars2<sup>V117L/V117L</sup></em> skeletal muscle and mouse embryonic fibroblasts.</p> <p>Overall, we have characterised the first mouse model of mitochondrial disease caused by a global, hypomorphic, mutation in an mtRS gene. We showed that the tissue-specific pathology observed in <em>Wars2<sup>V117L/V117L</sup></em> mice was due to activation of tissue-specific stress response mechanisms that either lead to disease pathology, such as activation of the ISR in the heart, or protection against inhibition of mitochondrial translation, such as up-regulation of <em>Pgc1a</em> in iWAT and MEFs. This study provides some evidence that up-regulation of mitochondrial biogenesis could be utilised as a therapeutic strategy to treat human patients with mtRS mutations in the future.</p>
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