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

被引：35

作者：

Agnew, Thomas ^{[1
,2
]}

Goldsworthy, Michelle ^{[1
,2
]}

Aguilar, Carlos ^{[1
,2
]}

Morgan, Anna ^{[1
,2
]}

Simon, Michelle ^{[1
,2
]}

Hilton, Helen ^{[1
,2
]}

Esapa, Chris ^{[1
,2
]}

Wu, Yixing ^{[1
,2
]}

Cater, Heather ^{[1
,2
]}

Bentley, Liz ^{[1
,2
]}

Scudamore, Cheryl ^{[1
,2
]}

Poulton, Joanna ^{[3
]}

Morten, Karl J. ^{[3
]}

Thompson, Kyle ^{[4
]}

He, Langping ^{[4
]}

Brown, Steve D. M. ^{[1
,2
]}

Taylor, Robert W. ^{[4
]}

Bowl, Michael R. ^{[1
,2
]}

Cox, Roger D. ^{[1
,2
]}

机构：

[1] Harwell Inst, MRC, Mammalian Genet Unit, Harwell Campus, Harwell OX11 0RD, Oxon, England

[2] Mary Lyon Ctr, Harwell Campus, Harwell OX11 0RD, Oxon, England

[3] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Obstet & Gynaecol, Womens Ctr, Level 3, Oxford OX3 9DU, England

[4] Newcastle Univ, Inst Neurosci, Med Sch, Wellcome Ctr Mitochondrial Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

来源：

CELL REPORTS | 2018年 / 25卷 / 12期

基金：

英国医学研究理事会; 英国工程与自然科学研究理事会;

关键词：

TRANSFER-RNA SYNTHETASE; RESPIRATORY-CHAIN DEFICIENCY; LACTIC-ACIDOSIS; HYPERTROPHIC CARDIOMYOPATHY; MITOCHONDRIAL MYOPATHY; HEARING-LOSS; MUTATIONS; FGF21; GENE; INDUCTION;

D O I：

10.1016/j.celrep.2018.11.080

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：3315 / +

页数：20

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