Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans.

Abstract

Transfer RNAs (tRNAs) contain a wide variety of posttranscriptional modifications that are important for accurate decoding. Mammalian mitochondrial tRNAs (mt-tRNAs) are modified by nuclear-encoded tRNA-modifying enzymes; however, the physiological roles of these modifications remain largely unknown. In this study, we report that Cdk5 regulatory subunit-associated protein 1 (Cdk5rap1) is responsible for 2-methylthio (ms(2)) modifications of mammalian mt-tRNAs for Ser(UCN), Phe, Tyr, and Trp codons. Deficiency in ms(2) modification markedly impaired mitochondrial protein synthesis, which resulted in respiratory defects in Cdk5rap1 knockout (KO) mice. The KO mice were highly susceptive to stress-induced mitochondrial remodeling and exhibited accelerated myopathy and cardiac dysfunction under stressed conditions. Furthermore, we demonstrate that the ms(2) modifications of mt-tRNAs were sensitive to oxidative stress and were reduced in patients with mitochondrial disease. These findings highlight the fundamental role of ms(2) modifications of mt-tRNAs in mitochondrial protein synthesis and their pathological consequences in mitochondrial disease.

• Authors: Fan-Yan Wei, Bo Zhou, Takeo Suzuki, Keishi Miyata, Yoshihiro Ujihara, Haruki Horiguchi, Nozomu Takahashi, Peiyu Xie, Hiroyuki Michiue, Atsushi Fujimura, Taku Kaitsuka, Hideki Matsui, Yasutoshi Koga, Satoshi Mohri, Tsutomu Suzuki, Yuichi Oike, Kazuhito Tomizawa
• Journal: Cell metabolism (Cell Metab) Vol. 21 Issue 3 Pg. 428-42 (Mar 03 2015) ISSN: 1932-7420 [Electronic] United States
• PMID: 25738458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Intracellular Signaling Peptides and Proteins
• Nerve Tissue Proteins
• RNA, Transfer
• CDK5RAP1 protein, human

Topics

• Animals
• Cells, Cultured
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Mitochondria (genetics)
• Mitochondrial Diseases (genetics)
• Muscular Diseases (genetics)
• Nerve Tissue Proteins (genetics)
• Oxidative Stress (genetics)
• Protein Biosynthesis (genetics)
• RNA Processing, Post-Transcriptional (genetics)
• RNA, Transfer (genetics)