Cardiomyocyte-derived GPX4 stabilizes BNIP3 to facilitate mitophagy and mitigate myocardial ischemia/reperfusion injury
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Lingfeng Zhong1,2,3,4,5, Zhenfeng Cheng6, Yucong Zhang1,2
1Department of Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Abstract:
GPX4 is a crucial regulator of ferroptosis, yet its role in mitochondrial dysfunction during myocardial ischemia/reperfusion injury (MI/RI) is unclear. This study aims to clarify the effect and molecular mechanisms of GPX4 in MI/RI. We analyzed the spatiotemporal dynamics of GPX4 during MI/RI and observed high expression levels in border and normal areas but a significant reduction in the ischemic region utilizing spatial transcriptomics, spatial proteomics, and single-cell sequencing. Cardiomyocyte-derived GPX4 notably reduces myocardial damage and mitochondrial dysfunction in MI/RI while also alleviating long-term ventricular remodeling. Mechanistically, our findings reveal that GPX4, through its critical U46 active site, enhances the interaction between BNIP3 and USP20, decreasing ubiquitination at K131 of BNIP3. This process stabilizes BNIP3, promotes mitophagy, improves mitochondrial function, and ultimately preserves cardiac function. Our research defines the role of the GPX4/BNIP3/USP20 complex in MI/RI and uncovers a mechanism linking GPX4 to ferroptosis-related mitochondrial damage, providing valuable insights for advancing ferroptosis studies.
Insights
Glutathione peroxidase 4 (GPX4) protects the heart during ischemia/reperfusion injury (MI/RI) by reducing mitochondrial damage. GPX4 stabilizes BNIP3, promoting mitophagy and preserving cardiac function.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Myocardial ischemia/reperfusion injury (MI/RI) involves significant mitochondrial dysfunction.
- The role of glutathione peroxidase 4 (GPX4) in MI/RI-induced mitochondrial damage is not fully understood.
- GPX4 is a key regulator of ferroptosis, a cell death pathway linked to oxidative stress.
Purpose of the Study:
- To investigate the effect and molecular mechanisms of GPX4 in myocardial ischemia/reperfusion injury (MI/RI).
- To elucidate the role of GPX4 in regulating mitochondrial function and ferroptosis during MI/RI.
Main Methods:
- Spatial transcriptomics, spatial proteomics, and single-cell sequencing were used to analyze GPX4 expression dynamics in MI/RI.
- Experimental models were employed to assess the impact of cardiomyocyte-derived GPX4 on myocardial damage and mitochondrial function.
- Molecular analyses were performed to identify the interaction partners and mechanisms involving GPX4.
Main Results:
- GPX4 expression was significantly reduced in the ischemic region of the heart during MI/RI.
- Cardiomyocyte-specific GPX4 overexpression mitigated myocardial damage, improved mitochondrial function, and reduced ventricular remodeling post-MI/RI.
- GPX4 was found to enhance the interaction between BNIP3 and USP20, reducing BNIP3 ubiquitination, stabilizing BNIP3, and promoting mitophagy.
Conclusions:
- GPX4 plays a protective role in MI/RI by preserving mitochondrial function and reducing ferroptosis-related damage.
- The GPX4/BNIP3/USP20 complex is a critical mediator of cardioprotection during MI/RI.
- Targeting the GPX4 pathway offers a potential therapeutic strategy for managing MI/RI and related cardiac conditions.
