Mitochondrial tRNA-specific Taurine Modifications Correlate With Ferroptosis-associated Myocardial Injury

Transfer RNA (tRNA) modifications are crucial for cellular homeostasis and organ function, exhibiting complex stress responses dependent on modification type and location. Ferroptosis, a significant mechanism in ischemic myocardial injury, remains poorly understood at the tRNA epitranscriptome level. In this study, we utilized a liquid chromatography-mass spectrometry (LC-MS) based RNA mapping platform to examine dynamic changes in 40 tRNA modifications within a ferroptosis-associated myocardial injury model. Notably, we identified significant in vitro and in vivo alterations in eight tRNA modifications, particularly a marked downregulation of taurine modifications (τm5U and τm5s2U) at the tRNA anticodon's 34th position, suggesting mitochondrial tRNA (mt-tRNATrp, mt-tRNAGln) reprogramming. Further analysis revealed that taurine modification depletion caused by RSL3 (a ferroptosis inducer) was attributed to taurine consumption and the downregulation of MTO1 and GTPBP3. Depleting these taurine modifications exacerbated ferroptosis in vitro, while restoration protected cardiomyocytes by decreasing reactive oxygen species and lipid peroxides. Silencing of MTO1 and GTPBP3 in H9C2 cells could also enhance RSL3 potency but diminish the protective effect of taurine. Our findings highlight the pivotal role of taurine modifications on mitochondrial tRNAs in determining cellular fate during cardiomyocyte ferroptosis. This study offers new insights into ferroptosis-associated ischemic myocardial injury at the tRNA epitranscriptome level.