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Published on: June 3, 2018
METTL3-mediated N6-methyladenosine modification of Dnajb1 modulates cardiomyocyte ferroptosis during myocardial
Shuchen Zhang1, Boyang Xiang1, Yiheng Zhao1
1Department of Cardiology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China.
Abstract:
Myocardial infarction (MI) affects millions of individuals worldwide, with ferroptosis recognized as a pivotal regulated cell death pathway in this context. N6-methyladenosine (m6A), the most prevalent mRNA modification, is essential in modulating RNA splicing, export, stability, and translation during MI progression. Nonetheless, the involvement of m6A modification in cardiomyocyte ferroptosis has yet to be elucidated. This study aimed to elucidate the regulatory mechanisms of m6A modification in cardiomyocyte ferroptosis by conducting an integrated analysis of methylated RNA immunoprecipitation-sequencing and RNA-sequencing data obtained from myocardial tissues of MI mice, to identify promising therapeutic strategies for MI. We demonstrated that the differentially m6A-modified DnaJ heat shock protein family member B1 (Dnajb1) gene suppressed ferroptosis during the pathological process of MI. DNAJB1 overexpression protected against hypoxia-induced cardiomyocyte ferroptosis by suppressing pro-ferroptotic effectors. Mechanistically, methyltransferase-like 3 (METTL3) bound to Dnajb1, enhancing its m6A modification and diminishing mRNA stability, while insulin-like growth factor 2 mRNA-binding protein 3 competes for binding and increases mRNA stability. DNAJB1 prevented hypoxia-induced glutathione depletion and lipid peroxidation by inhibiting glutathione peroxidase 4 degradation via the autophagic-lysosomal pathway. In vivo, DNAJB1 overexpression improved heart function, reduced infarct size and fibrosis, and lowered plasma malondialdehyde levels in MI mice, whereas METTL3 co-overexpression counteracted these cardioprotective effects. Overall, this study uncovers a METTL3/Dnajb1 pathway in cardiomyocyte ferroptosis during MI. METTL3 modifies Dnajb1 through m6A, destabilizing its mRNA and weakening glutathione peroxidase 4-dependent antioxidant defense, thus promoting ferroptosis. These insights into epitranscriptomic regulation of cell death highlight potential therapeutic targets to prevent ferroptosis-related cardiac damage.
Insights
The METTL3/Dnajb1 pathway regulates ferroptosis in heart attacks. METTL3-induced m6A modification of Dnajb1 mRNA promotes ferroptosis, while Dnajb1 protects against heart damage.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Cell Death Mechanisms
Background:
- Myocardial infarction (MI) is a leading cause of death globally.
- Ferroptosis, a regulated cell death pathway, plays a critical role in MI pathogenesis.
- N6-methyladenosine (m6A) modification influences RNA metabolism and is implicated in various diseases, but its role in cardiomyocyte ferroptosis during MI remains unclear.
Purpose of the Study:
- To investigate the role of m6A modification in cardiomyocyte ferroptosis during MI.
- To elucidate the regulatory mechanisms of m6A modification in ferroptosis.
- To identify potential therapeutic targets for MI.
Main Methods:
- Integrated analysis of methylated RNA immunoprecipitation-sequencing (m6A-IP-seq) and RNA-sequencing (RNA-seq) data from MI mouse models.
- In vitro studies on cardiomyocyte ferroptosis using overexpression and knockdown techniques.
- In vivo validation in MI mouse models to assess cardiac function and pathology.
Main Results:
- The DnaJ heat shock protein family member B1 (Dnajb1) gene was identified as differentially m6A-modified and found to suppress ferroptosis.
- Overexpression of DNAJB1 protected cardiomyocytes against hypoxia-induced ferroptosis by inhibiting pro-ferroptotic effectors and preserving glutathione levels.
- Mechanistically, methyltransferase-like 3 (METTL3) enhanced m6A modification of Dnajb1, reducing its mRNA stability, while insulin-like growth factor 2 mRNA-binding protein 3 competed for binding, increasing stability. DNAJB1 inhibited glutathione peroxidase 4 degradation, preventing ferroptosis.
Conclusions:
- A novel METTL3/Dnajb1 pathway regulating cardiomyocyte ferroptosis in MI was uncovered.
- METTL3-mediated m6A modification of Dnajb1 destabilizes its mRNA, impairs antioxidant defense, and promotes ferroptosis.
- Targeting this epitranscriptomic pathway offers potential therapeutic strategies for preventing ferroptosis-related cardiac damage in MI.
