METTL1‐Mediated N 7 ‐Methylguanosine tRNA Modification Alleviates Cardiac Ischemia/Reperfusion Injury by Modulating Mitochondrial Energy Metabolism

ABSTRACT Ischemic heart disease is one of the diseases with the highest morbidity and mortality in the world. The N 7 ‐methylguanosine (m 7 G) tRNA modifications are widely recognized as one of the most prevalent tRNA modifications. Nevertheless, there is still a lack of understanding regarding the roles and molecular mechanisms underlying the METTL1‐mediated m 7 G tRNA modification in cardiac ischemia/reperfusion (I/R) injury. METTL1 and m 7 G tRNA modification were upregulated in mice with I/R injury hearts and the plasma of patients with acute myocardial infarction. Thus, we constructed METTL1 knockout mice and found that silencing METTL1 alleviates I/R. Mechanistically, tRNA sequencing, MeRIP‐m 7 G‐tRNA sequencing, and Ribosome profiling sequencing were used to clarify deficiency of METTL1 reduced the levels of m 7 G tRNA modifications and m 7 G‐modified tRNAs, and consequently, downregulated the translation efficiency of ATPIF1 mRNA to restore the level of mitochondrial oxidative phosphorylation and suppress the increase of mitochondrial apoptosis. Moreover, cardiac‐specific overexpression of ATPIF1 induced myocardial hypertrophy and inhibited the protective effect of silencing METTL1 on cardiac I/R injury. Collectively, m 7 G tRNA modifications regulate the translation efficiency of ATPIF1, which eventually mediates mitochondrial energy metabolism, apoptosis, and myocardial I/R injury. The findings uncover that interfering with METTL1 and ATPIF1 represents a novel therapeutic target in myocardial I/R injury.