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Among several leading cardiovascular disorders, ischemia–reperfusion (I/R) injury causes severe manifestations including acute heart failure and systemic dysfunction. Recently, there has been increasing evidence suggesting that alterations in mitochondrial morphology and dysfunction also play an important role in the prognosis of cardiac disorders. Long non-coding RNAs (lncRNAs) form major regulatory networks altering gene transcription and translation. While the role of lncRNAs has been extensively studied in cancer and tumor biology, their implications on mitochondrial morphology and functions remain to be elucidated. In this study, the functional roles of Zinc finger protein 36-like 2 (ZFP36L2) and lncRNA PVT1 were determined in cardiomyocytes under hypoxia/reoxygenation (H/R) injury in vitro and myocardial I/R injury in vivo. Western blot and qRT-PCR analysis were used to assess the levels of ZFP36L2, mitochondrial fission and fusion markers in the myocardial tissues and cardiomyocytes. Cardiac function was determined by immunohistochemistry, H&E staining, and echocardiogram. Ultrastructural analysis of mitochondrial fission was performed using transmission electron microscopy. The mechanistic model consisting of PVT1 with ZFP36L2 and microRNA miR-21-5p with E3 ubiquitin ligase MARCH5 was assessed by subcellular fraction, RNA pull down, FISH, and luciferase reporter assays. These results identified a novel regulatory axis involving PVT1, miR-21-5p, and MARCH5 that alters mitochondrial morphology and function during myocardial I/R injury. Using an in vivo I/R injury mouse model and in vitro cardiomyocytes H/R model, we demonstrated that ZFP36L2 directly associates with PVT1 and alters mitochondrial fission and fusion. PVT1 also interactes with miR-21-5p and suppresses its expression and activity. Furthermore, we identified MARCH5 as a modifier of miR-21-5p, and its effect on mitochondrial fission and fusion are directly proportional to PVT1 expression during H/R injury. Our findings show that manipulation of PVT1-miR-21-5p-MARCH5-mediated mitochondrial fission and fusion via ZFP36L2 may be a novel therapeutic approach to regulate myocardial I/R injury.

ZFP36L2 regulates myocardial ischemia/reperfusion injury and attenuates mitochondrial fusion and fission by LncRNA PVT1