| Summary: | Summary: Mutations in genes essential for mitochondrial function have pleiotropic effects. The mechanisms underlying these traits yield insights into metabolic homeostasis and potential therapies. Here we report the characterization of a mouse model harboring a mutation in the tryptophanyl-tRNA synthetase 2 (Wars2) gene, encoding the mitochondrial-localized WARS2 protein. This hypomorphic allele causes progressive tissue-specific pathologies, including hearing loss, reduced adiposity, adipose tissue dysfunction, and hypertrophic cardiomyopathy. We demonstrate the tissue heterogeneity arises as a result of variable activation of the integrated stress response (ISR) pathway and the ability of certain tissues to respond to impaired mitochondrial translation. Many of the systemic metabolic effects are likely mediated through elevated fibroblast growth factor 21 (FGF21) following activation of the ISR in certain tissues. These findings demonstrate the potential pleiotropy associated with Wars2 mutations in patients. : A reduced-function mutation in the nuclear-encoded, mitochondrial-localized Wars2 gives rise to deafness, reduced and abnormal fat, and hypertrophic cardiomyopathy. Agnew et al. show that the different tissue effects of this mutation arise from variable activation of stress response pathways and tissue-specific responses to impaired mitochondrial function. Keywords: WARS2, deafness, adiposity, hypertrophic cardiomyopathy, pleiotropic, ISR, mitochondrial dysfunction
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