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

• DOI: 10.1016/j.celrep.2018.11.080
• Publication Date: 2018-12-18T15:39:57Z
• Authors: Thomas Agnew; Michelle Goldsworthy; Carlos Aguilar; Anna Morgan; Michelle Simon; Helen Hilton; Chris Esapa; Yixing Wu; Heather Cater; Liz Bentley; Cheryl Scudamore; Joanna Poulton; Karl J. Morten; Kyle Thompson; Langping He; Steve D.M. Brown; Robert W. Taylor; Michael R. Bowl; Roger D. Cox
• Keywords: FGF21

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 mutation tryptophanyl-tRNA synthetase 2 (Wars2) gene, encoding mitochondrial-localized WARS2 protein. This hypomorphic allele causes progressive tissue-specific pathologies, including hearing loss, reduced adiposity, adipose tissue dysfunction, hypertrophic cardiomyopathy. We demonstrate heterogeneity arises as result variable activation integrated stress response (ISR) pathway ability certain tissues to respond impaired translation. Many systemic effects are likely mediated through elevated fibroblast growth factor 21 (FGF21) following ISR tissues. These findings pleiotropy associated with Wars2 mutations patients.