Nuclear receptor 4A1 Regulates Mitochondrial Homeostasis in Cardiac Post-Ischemic Injury by Controlling Mitochondrial Fission 1 Protein-Mediated Fragmentation and Parkin-Dependent Mitophagy.

Autor:	Ye H; Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120., Lin J; Department of Cardiovascular Medicine, The Fourth Affiliated Hospital of Guangzhou Medical University, Zengcheng District People's Hospital of Guangzhou, Guangzhou, China, 511300., Zhang H; Guang'anmen Hospital China Academy of Chinese Medical Sciences, China., Wang J; Xianning Medical College, Hubei University of Science & Technology, Xianning 437000, China., Fu Y; Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120., Zeng Z; Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120., Zheng J; Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120., Tao J; Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120., Qiu J; Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120.
Jazyk:	angličtina
Zdroj:	International journal of biological sciences [Int J Biol Sci] 2025 Jan 01; Vol. 21 (1), pp. 400-414. Date of Electronic Publication: 2025 Jan 01 (Print Publication: 2025).
DOI:	10.7150/ijbs.104680
Abstrakt:	The close interaction of mitochondrial fission and mitophagy, two crucial mechanisms, is key in the progression of myocardial ischemia-reperfusion (IR) injury. However, the upstream regulatory mechanisms governing these processes remain poorly understood. Here, we demonstrate a marked elevation in Nr4a1 expression following myocardial IR injury, which is associated with impaired cardiac function, heightened cardiomyocyte apoptosis, exacerbated inflammatory responses, and endothelial dysfunction. Notably, Nr4a1-knockout mice exhibited remarkable resistance to acute myocardial IR injury, characterized by preserved mitochondrial integrity relative to their wild-type counterparts. Functional analyses revealed that elevated Nr4a1 expression after IR injury promotes Fis1-mediated mitochondrial fission while suppressing Parkin-driven mitophagy. Importantly, interventions that inhibit mitochondrial fission or enhance mitophagy effectively ameliorated IR-induced cardiomyocyte and endothelial dysfunction. Collectively, these results highlight that the absence of Nr4a1 provides a shield against cardiac post-ischemic damage by reinstating balance within the mitochondria through inhibiting Fis1-induced fission and promoting Parkin-triggered mitophagy. Furthermore, therapeutic strategies targeting the Nr4a1/mitochondria axis may offer promising avenues for improving cardiac outcomes under myocardial IR stress. Competing Interests: Competing Interests: The authors have declared that no competing interest exists. (© The author(s).)
Databáze:	MEDLINE
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