# METTL1‐Mediated N7‐Methylguanosine tRNA Modification Alleviates Cardiac Ischemia/Reperfusion Injury by Modulating Mitochondrial Energy Metabolism

## TL;DR

This study shows that METTL1 and tRNA modifications worsen heart injury after blood flow returns, and blocking them could be a new treatment.

## Contribution

The study reveals METTL1-mediated m7G tRNA modification as a novel regulator of mitochondrial energy metabolism in cardiac I/R injury.

## Key findings

- METTL1 and m7G tRNA modification are upregulated in cardiac I/R injury.
- Reducing METTL1 improves mitochondrial function and reduces cardiac injury.
- m7G tRNA modifications regulate ATPIF1 translation, affecting mitochondrial apoptosis.

## Abstract

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.

During cardiac I/R injury, the level of METTL1 and tRNA m7G modification increases and then leads to CMs’ mitochondrial dysfunction and aggravated cardiac injury by modulating the transcription efficiency of ATPIF1.