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

• DOI: 10.1073/pnas.2309714120
• Publication Date: 2023-09-05T17:52:22Z
• Authors: Wen-Qiang Zheng; Jian-Hui Zhang; Zi-Han Li; Xiuxiu Liu; Yong Zhang; Shuo Huang; Jinsong Li; Bin Zhou; Gilbert Eriani; En-Duo Wang; Xiao-Long Zhou
• Keywords: Amino Acyl-tRNA Synthetases; Mammals; Mice; Oxidative Stress; Heart Diseases; Animals; Cell Cycle Checkpoints; Biological Sciences; Reactive Oxygen Species; Cardiomyopathies

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