Nsun2-mediated m5C methylation of Ncor1 exacerbates sepsis-induced cardiomyopathy by promoting mitochondrial dysfunction.

Abstract

Sepsis-induced cardiomyopathy (SIC) is a severe complication of sepsis characterized by mitochondrial dysfunction and impaired myocardial contractility, yet its molecular pathogenesis remains incompletely understood. In this study, we demonstrate that excessive mitochondrial fission plays a pivotal role in SIC, contributing to inflammation, oxidative stress, and cardiomyocyte apoptosis. Pharmacological inhibition of mitochondrial fission using Mdivi-1 alleviated these pathological changes both in vivo and in vitro. Bioinformatic analyses of public datasets identified nuclear receptor corepressor 1 (Ncor1) as a key mitochondrial dynamics-related gene upregulated in SIC. Lentiviral knockdown of Ncor1 mitigated myocardial injury and restored mitochondrial homeostasis in both lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) induced SIC mouse model. Mechanistically, we found that the RNA m5C methyltransferase Nsun2 was significantly upregulated in SIC and enhanced Ncor1 mRNA stability via m5C methylation through reading protein ALYREF. Functional experiments revealed that Nsun2 knockdown ameliorated cardiomyocyte injury, while co-knockdown of Ncor1 reversed the deleterious effects of Nsun2 overexpression. Collectively, our findings reveal a novel Nsun2/Ncor1 axis that drives mitochondrial dysfunction in SIC through epitranscriptomic regulation, providing potential therapeutic targets for septic cardiac injury.