Conformational change in transfer RNA is an early indicator of acute cellular damage

Eikan Mishima, Chisako Inoue, Daisuke Saigusa, Ryusuke Inoue, Koki Ito, Yusuke Suzuki, Daisuke Jinno, Yuri Tsukui, Yosuke Akamatsu, Masatake Araki, Kimi Araki, Ritsuko Shimizu, Haruka Shinke, Takehiro Suzuki, Yoichi Takeuchi, Hisato Shima, Yasutoshi Akiyama, Takafumi Toyohara, Chitose Suzuki, Yoshikatu SaikiTeiji Tominaga, Shigehito Miyagi, Naoki Kawagisihi, Tomoyoshi Soga, Takayoshi Ohkubo, Kenichi Yamamura, Yutaka Imai, Satohiro Masuda, Venkata Sabbisetti, Takaharu Ichimura, David B. Mount, Joseph V. Bonventre, Sadayoshi Ito, Yoshihisa Tomioka, Kunihiko Itoh, Takaaki Abe

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Tissue damage by oxidative stress is a key pathogenic mechanism in various diseases, including AKI and CKD. Thus, early detection of oxidative tissue damage is important. Using a tRNA-specific modified nucleoside 1-methyladenosine (m1A) antibody, we show that oxidative stress induces a direct conformational change in tRNA structure that promotes subsequent tRNA fragmentation and occurs much earlier than DNA damage. In variousmodels of tissue damage (ischemic reperfusion, toxic injury, and irradiation), the levels of circulating tRNA derivatives increased rapidly. In humans, the levels of circulating tRNA derivatives also increased under conditions of acute renal ischemia, even before levels of other known tissue damage markers increased. Notably, the level of circulating free m1A correlated with mortality in the general population (n=1033) over a mean follow-up of 6.7 years. Compared with healthy controls, patients with CKD had higher levels of circulating free m1A, which were reduced by treatment with pitavastatin (2 mg/d; n=29). Therefore, tRNA damage reflects early oxidative stress damage, and detection of tRNA damage may be a useful tool for identifying organ damage and forming a clinical prognosis.

Original languageEnglish
Pages (from-to)2316-2326
Number of pages11
JournalJournal of the American Society of Nephrology
Volume25
Issue number10
DOIs
Publication statusPublished - 2014 Oct 1

ASJC Scopus subject areas

  • Nephrology

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    Mishima, E., Inoue, C., Saigusa, D., Inoue, R., Ito, K., Suzuki, Y., Jinno, D., Tsukui, Y., Akamatsu, Y., Araki, M., Araki, K., Shimizu, R., Shinke, H., Suzuki, T., Takeuchi, Y., Shima, H., Akiyama, Y., Toyohara, T., Suzuki, C., ... Abe, T. (2014). Conformational change in transfer RNA is an early indicator of acute cellular damage. Journal of the American Society of Nephrology, 25(10), 2316-2326. https://doi.org/10.1681/ASN.2013091001