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

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.