CO2-sensitive tRNA modification associated with human mitochondrial disease

Nat Commun. 2018 May 14;9(1):1875. doi: 10.1038/s41467-018-04250-4.

Huan Lin ¹, Kenjyo Miyauchi ¹, Tai Harada ¹, Ryo Okita ¹, Eri Takeshita ² ³, Hirofumi Komaki ² ³, Kaoru Fujioka ⁴, Hideki Yagasaki ⁴, Yu-Ichi Goto ² ³ ⁵, Kaori Yanaka ⁶, Shinichi Nakagawa ⁶ ⁷, Yuriko Sakaguchi ¹, Tsutomu Suzuki ⁸

Affiliations

1 Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
2 Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.
3 Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.
4 Department of Pediatrics, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, Yamanashi, 409-3898, Japan.
5 Medical Genome Center, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.
6 RNA Biology Laboratory, RIKEN Advanced Research Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
7 RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo Nishi 6-chome, Kita-ku, Sapporo, 060-0812, Japan.
8 Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan. ts@chembio.t.u-tokyo.ac.jp.

PMID: 29760464 DOI: 10.1038/s41467-018-04250-4

Abstract

It has been generally thought that tRNA modifications are stable and static, and their frequencies are rarely regulated. N⁶-threonylcarbamoyladenosine (t⁶A) occurs at position 37 of five mitochondrial (mt-)tRNA species. We show that YRDC and OSGEPL1 are responsible for t⁶A37 formation, utilizing L-threonine, ATP, and CO₂/bicarbonate as substrates. OSGEPL1-knockout cells exhibit respiratory defects and reduced mitochondrial translation. We find low level of t⁶A37 in mutant mt-tRNA isolated from the MERRF-like patient's cells, indicating that lack of t⁶A37 results in pathological consequences. Kinetic measurements of t⁶A37 formation reveal that the Km value of CO₂/bicarbonate is extremely high (31 mM), suggesting that CO₂/bicarbonate is a rate-limiting factor for t⁶A37 formation. Consistent with this, we observe a low frequency of t⁶A37 in mt-tRNAs isolated from human cells cultured without bicarbonate. These findings indicate that t⁶A37 is regulated by sensing intracellular CO₂/bicarbonate concentration, implying that mitochondrial translation is modulated in a codon-specific manner under physiological conditions.

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