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Nsun2-mediated m5C methylation of Ncor1 exacerbates sepsis-induced cardiomyopathy by promoting mitochondrial
Chan Chen1, Qing Liu1, Junmei Xu1
1Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
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.
Insights
Excessive mitochondrial fission contributes to sepsis-induced cardiomyopathy (SIC). Targeting the Nsun2/Ncor1 axis via epigenetic regulation offers a potential therapeutic strategy for septic cardiac injury.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Biology
- Molecular Medicine
Background:
- Sepsis-induced cardiomyopathy (SIC) involves mitochondrial dysfunction and impaired heart contractility.
- The precise molecular mechanisms driving SIC pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the role of mitochondrial dynamics in SIC.
- To identify key molecular players and pathways involved in SIC.
- To explore potential therapeutic targets for SIC.
Main Methods:
- Utilized in vivo and in vitro models of SIC, including lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) mouse models.
- Employed pharmacological inhibition of mitochondrial fission (Mdivi-1) and lentiviral-mediated gene knockdown (Ncor1, Nsun2).
- Performed bioinformatic analyses of public datasets and assessed molecular mechanisms including m5C methylation and mRNA stability.
Main Results:
- Excessive mitochondrial fission was identified as a critical factor in SIC, promoting inflammation, oxidative stress, and cardiomyocyte apoptosis.
- Pharmacological inhibition of mitochondrial fission attenuated SIC pathology.
- Nuclear receptor corepressor 1 (Ncor1) was upregulated in SIC and its knockdown mitigated myocardial injury.
- The RNA m5C methyltransferase Nsun2 was upregulated and enhanced Ncor1 mRNA stability via m5C methylation.
- Nsun2 knockdown ameliorated cardiomyocyte injury, while Ncor1 knockdown reversed Nsun2 overexpression effects.
Conclusions:
- A novel Nsun2/Ncor1 axis drives mitochondrial dysfunction in SIC through epigenetic regulation.
- This axis represents a potential therapeutic target for mitigating septic cardiac injury.
