METTL1-Mediated N⁷-Methylguanosine tRNA Modification Alleviates Cardiac Ischemia/Reperfusion Injury by Modulating...

Ischemic heart disease is one of the diseases with the highest morbidity and mortality in the world. The N⁷-methylguanosine (m⁷G) 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 m⁷G tRNA modification in cardiac ischemia/reperfusion (I/R) injury. METTL1 and m⁷G 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-m⁷G-tRNA sequencing, and Ribosome profiling sequencing were used to clarify deficiency of METTL1 reduced the levels of m⁷G tRNA modifications and m⁷G-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, m⁷G 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.