METTL1-Mediated N⁷ -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 N⁷ -methylguanosine (m⁷ 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 m⁷ G tRNA modification in cardiac ischemia/reperfusion (I/R) injury. METTL1 and m⁷ 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-m⁷ G-tRNA sequencing, and Ribosome profiling sequencing were used to clarify deficiency of METTL1 reduced the levels of m⁷ G tRNA modifications and m⁷ 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, m⁷ 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.

Keywords

myocardial ischemia/reperfusion injury / mitochondrial energy metabolism / METTL1 / m⁷G tRNA modification

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