Mammalian mitochondrial translation infidelity leads to oxidative stress–induced cell cycle arrest and cardiomyopathy

Author:

Zheng Wen-Qiang12,Zhang Jian-Hui13,Li Zi-Han1,Liu Xiuxiu1,Zhang Yong1,Huang Shuo12,Li Jinsong13,Zhou Bin13,Eriani Gilbert4,Wang En-Duo12,Zhou Xiao-Long13ORCID

Affiliation:

1. Key Laboratory of RNA Science and Engineering, State Key Laboratory of Molecular Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China

2. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China

3. Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China

4. Architecture et Réactivité de l’ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, Strasbourg 67084, France

Abstract

Proofreading (editing) of mischarged tRNAs by cytoplasmic aminoacyl-tRNA synthetases (aaRSs), whose impairment causes neurodegeneration and cardiac diseases, is of high significance for protein homeostasis. However, whether mitochondrial translation needs fidelity and the significance of editing by mitochondrial aaRSs have been unclear. Here, we show that mammalian cells critically depended on the editing of mitochondrial threonyl-tRNA synthetase (mtThrRS, encoded by Tars2 ), disruption of which accumulated Ser-tRNA Thr and generated a large abundance of Thr-to-Ser misincorporated peptides in vivo. Such infidelity impaired mitochondrial translation and oxidative phosphorylation, causing oxidative stress and cell cycle arrest in the G0/G1 phase. Notably, reactive oxygen species (ROS) scavenging by N-acetylcysteine attenuated this abnormal cell proliferation. A mouse model of heart-specific defective mtThrRS editing was established. Increased ROS levels, blocked cardiomyocyte proliferation, contractile dysfunction, dilated cardiomyopathy, and cardiac fibrosis were observed. Our results elucidate that mitochondria critically require a high level of translational accuracy at Thr codons and highlight the cellular dysfunctions and imbalance in tissue homeostasis caused by mitochondrial mistranslation.

Funder

the national key research and development program of China

the National Sicence Foundation of China

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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