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Cell Rep. 2018 Dec 18;25(12):3315-3328.e6. doi: 10.1016/j.celrep.2018.11.080.

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

Author information

1
MRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire OX11 0RD, UK.
2
Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Level 3 The Women's Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.
3
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
4
MRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire OX11 0RD, UK. Electronic address: m.bowl@har.mrc.ac.uk.
5
MRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire OX11 0RD, UK. Electronic address: r.cox@har.mrc.ac.uk.

Abstract

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.

KEYWORDS:

ISR; WARS2; adiposity; deafness; hypertrophic cardiomyopathy; mitochondrial dysfunction; pleiotropic

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