Ischemic Postconditioning Protects Aged Myocardium Against Ischemia/Reperfusion Injury by Regulating Mitochondrial Dynamics via piR‐4913
Xiangyu Zhao, Yanchun Li, Nan Li, Juan Zhang, Xiaolong Ma, Fei Yang, Ruihan Long, Yining Tian, Yichen Wang, Shengchao Ma, Huiping Zhang, Yideng JiangABSTRACT
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.