Ischemic Postconditioning Protects Aged Myocardium Against Ischemia/Reperfusion Injury by Regulating Mitochondrial Dynamics via piR‐4913

Ischemic postconditioning (IPostC) mitigates myocardial ischemia/reperfusion (I/R) injury, but its regulation of mitochondrial dynamics in the aged heart remains unclear. This study investigates the underlying mechanisms by evaluating PIWI-interacting RNA (piRNA) expression profiles after I/R injury. Functional assays using piR-4913 silencing assess its impact on infarct size, mitochondrial ATP production, and oxidative stress. Mechanistic analyses identify that piR-4913, a cardiac-enriched piRNA markedly upregulated in aged hearts following I/R injury, is effectively suppressed by IPostC. Silencing piR-4913 confers cardioprotection by limiting infarct size, enhancing ATP production, and reducing oxidative stress. Mechanistically, piR-4913 acts as a key facilitator that promotes the recruitment of OGT to Drp1, thereby catalyzing the O-GlcNAcylation modification of Drp1 at Thr604. This modification promotes Drp1 mitochondrial translocation and Fis1 interaction, driving excessive mitochondrial fission and dysfunction. In vivo validation using a Drp1-T604A mutant demonstrates profound resistance to I/R injury, confirming the critical role of Thr604 O-GlcNAcylation in age-related cardiac damage. Collectively, IPostC exerts cardioprotection in the aging heart by restraining the piR-4913/OGT/Drp1 axis, thereby restoring mitochondrial proteostasis and dynamics. This pathway represents a promising therapeutic target to improve clinical outcomes in elderly patients with myocardial infarction.