CO2-sensitive tRNA modification associated with human mitochondrial disease

Huan Lin, Kenjyo Miyauchi, Tai Harada, Ryo Okita, Eri Takeshita, Hirofumi Komaki, Kaoru Fujioka, Hideki Yagasaki, Yu-ichi Goto, Kaori Yanaka, Shinichi Nakagawa, Yuriko Sakaguchi and Tsutomu Suzuki ()
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Huan Lin: University of Tokyo
Kenjyo Miyauchi: University of Tokyo
Tai Harada: University of Tokyo
Ryo Okita: University of Tokyo
Eri Takeshita: National Center of Neurology and Psychiatry
Hirofumi Komaki: National Center of Neurology and Psychiatry
Kaoru Fujioka: University of Yamanashi
Hideki Yagasaki: University of Yamanashi
Yu-ichi Goto: National Center of Neurology and Psychiatry
Kaori Yanaka: RIKEN Advanced Research Institute
Shinichi Nakagawa: RIKEN Advanced Research Institute
Yuriko Sakaguchi: University of Tokyo
Tsutomu Suzuki: University of Tokyo

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04250-4

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