Abstract 6980: Peroxynitrite-Mediated Mitochondrial Autophagy is Activated for the Development of Global Cerebral Ischemia Induced by Cardiac Arrest

Abstract

Introduction: Mitochondrial dysfunction is implicated in ischemic brain after cardiac arrest, and the timely removal of damaged mitochondria is critical for cellular homeostasis. Mitochondrial autophagy is a mitochondrial quality control mechanism via selective degradation of mitochondria but its role in the ischemic brain remains controversial. Peroxynitrite, as a representative of reactive nitrogen species, is an important neurologic damage factor in the brain injury but its role in cardiac arrest is unknown. Methods: Male Sprague-Dawley rats underwent 8-minute asphyxial cardiac arrest and cardiopulmonary resuscitation. Survival, neurological deficit and mitochondrial function were assessed for up to 72 hours following cardiac arrest. Western blotting, immunofluorescence and enzyme-linked immunosorbent assay were used to evaluate activated mitochondrial autophagy and peroxynitrite production. To further explore the underlying mechanism, FeTMPyP was used to act as a peroxynitrite decomposition catalyst. Results: After resuscitation from cardiac arrest, PINK1/Parkin-induced mitochondrial autophagy was activated and peroxynitrite was increased in the ischemic brain. Peroxynitrite scavenger with FeTMPyP treatment significantly prevented the generation of peroxynitrite, inhibited mitochondrial autophagy activation, reduced neurological damages and improved mitochondrial and neurological outcome after cardiac arrest. Moreover, peroxynitrite induced serine 616 phosphorylation of Drp1 and Drp1 translocation to the mitochondria, which was responsible for mitochondrial autophagy activation. Conclusions: Mitochondrial autophagy activation mediated by peroxynitrite could be a key event in the pathogenesis of brain injury induced by cardiac arrest and provides a promising therapeutic strategy.