Details

Autor(en) / Beteiligte

• Wei, Fan-Yan
• Zhou, Bo
• Suzuki, Takeo
• Miyata, Keishi
• Ujihara, Yoshihiro
• Horiguchi, Haruki
• Takahashi, Nozomu
• Xie, Peiyu
• Michiue, Hiroyuki
• Fujimura, Atsushi
• Kaitsuka, Taku
• Matsui, Hideki
• Koga, Yasutoshi
• Mohri, Satoshi
• Suzuki, Tsutomu
• Oike, Yuichi
• Tomizawa, Kazuhito

Titel

Cdk5rap1-Mediated 2-Methylthio Modification of Mitochondrial tRNAs Governs Protein Translation and Contributes to Myopathy in Mice and Humans

Ist Teil von

• Cell metabolism, 2015-03, Vol.21 (3), p.428-442

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (ms2) modifications of mammalian mt-tRNAs for Ser(UCN), Phe, Tyr, and Trp codons. Deficiency in ms2 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 ms2 modifications of mt-tRNAs were sensitive to oxidative stress and were reduced in patients with mitochondrial disease. These findings highlight the fundamental role of ms2 modifications of mt-tRNAs in mitochondrial protein synthesis and their pathological consequences in mitochondrial disease. [Display omitted] •Cdk5rap1 catalyzes 2-methylthio (ms2) modification of four mitochondrial tRNAs•The ms2 modifications optimize mitochondrial translation and OXPHOS activity•Deficiency of ms2 modification accelerates myopathy and cardiac dysfunction in mice•The ms2 modification levels are reduced in patients with mitochondrial disease Wei et al. report that Cdk5rap1 is responsible for 2-methylthio (ms2) modifications of mammalian mt-tRNAs. The modification is critical for efficient mitochondrial translation in mice and dysregulated in MELAS patients.