METTL3 boosts mitochondrial fission and induces cardiac fibrosis after ischemia/reperfusion injury.

ABSTRACT

METTL3, an RNA methyltransferase enzyme, exerts therapeutic effects on various cardiovascular diseases. Myocardial ischemia-reperfusion injury (MIRI) and subsequently cardiac fibrosis is linked to acute cardiomyocyte death or dysfunction induced by mitochondrial damage, particularly mitochondrial fission. Our research aims to elucidate the potential mechanisms underlying the therapeutic actions of METTL3 in MIRI, with focus on mitochondrial fission. When compared with Mettl3flox mice subjected to MIRI, Mettl3 cardiomyocyte knockout (Mettl3Cko) mice have reduced infarct size, decreased serum levels of myocardial injury-related factors, limited cardiac fibrosis, and preserved myocardial ultrastructure and contractile/relaxation capacity. The cardioprotective actions of Mettl3 knockout were associated with reduced inflammatory responses, decreased myocardial neutrophil infiltration, and suppression of cardiomyocyte death. Through signaling pathway validation experiments and assays in cultured HL-1 cardiomyocytes exposed to hypoxia/reoxygenation, we confirmed that Mettl3 deficiency interfere with DNA-PKcs phosphorylation, thereby blocking the downstream activation of Fis1 and preventing pathological mitochondrial fission. In conclusion, this study confirms that inhibition of METTL3 can alleviate myocardial cardiac fibrosis inflammation and prevent cardiomyocyte death under reperfusion injury conditions by disrupting DNA-PKcs/Fis1-dependent mitochondrial fission, ultimately improving cardiac function. These findings suggest new approaches for clinical intervention in patients with MIRI.