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A Wars2 Mutant Mouse Model Displays OXPHOS Deficiencies and Activation of Tissue-Specific Stress Response Pathways

Lookup NU author(s): Dr Kyle Thompson, Dr Langping He, Professor Robert Taylor

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2018 The Author(s) 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.


Publication metadata

Author(s): Agnew T, Goldsworthy M, Aguilar C, Morgan A, Simon M, Hilton H, Esapa C, Wu Y, Cater H, Bentley L, Scudamore C, Poulton J, Morten KJ, Thompson K, He L, Brown SDM, Taylor RW, Bowl MR, Cox RD

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2018

Volume: 25

Issue: 12

Pages: 3315-3328.e6

Print publication date: 18/12/2018

Online publication date: 18/12/2018

Acceptance date: 21/11/2018

ISSN (electronic): 2211-1247

Publisher: Elsevier B.V.

URL: https://doi.org/10.1016/j.celrep.2018.11.080

DOI: 10.1016/j.celrep.2018.11.080


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