Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans.
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.
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Fan-Yan
FY
Wei
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Bo
B
Zhou
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan.
Takeo
T
Suzuki
Department of Molecular Genetics, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Keishi
K
Miyata
First Department of Physiology, Kawasaki Medical School, Okayama 701-0192, Japan.
Yoshihiro
Y
Ujihara
Department of Molecular Genetics, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Haruki
H
Horiguchi
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Nozomu
N
Takahashi
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Peiyu
P
Xie
Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Hiroyuki
H
Michiue
Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Atsushi
A
Fujimura
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Taku
T
Kaitsuka
Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Hideki
H
Matsui
Department of Pediatrics and Child Health, Kurume University Graduate School of Medicine, Fukuoka 830-0011, Japan.
Yasutoshi
Y
Koga
First Department of Physiology, Kawasaki Medical School, Okayama 701-0192, Japan.
Satoshi
S
Mohri
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan.
Tsutomu
T
Suzuki
Department of Molecular Genetics, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Yuichi
Y
Oike
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan. Electronic address: tomikt@kumamoto-u.ac.jp.
Kazuhito
K
Tomizawa
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics*; D009135:Muscular Diseases / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D012343:RNA, Transfer / Q000235:genetics*; D019885:Sulfur Group Transferases; D024101:Mitochondrial Proteins
D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D012343:RNA, Transfer; C405930:CDK5RAP1 protein, human; D019885:Sulfur Group Transferases; D024101:Mitochondrial Proteins