Conformational Change in Transfer RNA Is an Early Indicator of Acute Cellular Damage

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 various models 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.

Angiogenin Mediates Cell-Autonomous Translational Control under Endoplasmic Reticulum Stress and Attenuates Kidney Injury

“…Our findings are consistent with those recently published indicating that, in various models of tissue damage (ischemic reperfusion, toxic injury and irradiation), the levels of circulating tRNA derivatives, which correspond to the conformational change in tRNA structure that occurs before fragmentation, increased rapidly and may serve as a marker of early tissue injury. 41 Together, these and our results suggest that tRNA derivates are likely involved in renal cell adaptation under stress and highlight the biologic relevance of tRNA catabolism in kidney injury.…”

The Piezo Actuator-Driven Pulsed Water Jet System for Minimizing Renal Damage after Off-Clamp Laparoscopic Partial Nephrectomy

“…Oxidative stress induces direct conformational change in tRNA structure and the change promotes subsequent tRNA fragmentation (Mishima et al 2014). Such tRNA changes occur much earlier than DNA fragmentation, suggesting that the conformational change in tRNA is a primary response to cell injury.…”

“…Serial 3-μm-thick sections were prepared, and their morphological features were then examined in paraffin sections with hematoxylin-eosin (HE) staining. The extents of renal ischemia and oxidative stress were examined by immunohistochemical staining for 1-methyladenosine (m1A) that is a transfer RNA-specific modified nucleoside and is highly sensitive to the oxidative tissue damage (Mishima et al 2014). The monoclonal antibody against m1A was used for early detection of resection surface damage, which is important to evaluate the effect of each surgical device.…”

Rapid and selective simultaneous quantitative analysis of modified nucleosides using multi-column liquid chromatography-tandem mass spectrometry

“…Using this unique surface property of the ADME column, we achieved good chromatographic separation of nucleosides and rapid analysis. Tubercidin was previously used as an internal standard (Mishima et al 2014). However, we used f 2 dA because it was not separated from other nucleosides under this chromatographic condition.…”