Mitophagy alleviates neuronal damage after subarachnoid hemorrhage: Role of autophagy-targeting chimera 4

Abstract This study investigated the role of autophagy-targeting chimera 4, a novel activator of autophagy that targets mitochondria, in a subarachnoid hemorrhage model. The data demonstrated that in an in vitro mitochondrial damage model, autophagy-targeting chimera 4 reversed carbonyl cyanide 3-chlorophenylhydrazone-induced mitochondrial membrane potential collapse and activated mitophagy. In the in vitro subarachnoid hemorrhage model, autophagy-targeting chimera 4 improved neuronal proliferation and migration during the acute phase and reduced neuronal apoptosis after subarachnoid hemorrhage. In the in vivo subarachnoid hemorrhage model, autophagy-targeting chimera 4 also decreased neuronal apoptosis during the acute phase, improved neurological function, and ultimately reduced long-term neuronal loss. Additionally, increased ring finger protein 144B expression after subarachnoid hemorrhage was associated with poor prognosis, and autophagy-targeting chimera 4 significantly inhibited ring finger protein 144B expression, thereby activating mitophagy and reducing neuronal apoptosis. The results also showed that the mitophagic marker parkin did not exert protective effects during the acute phase after subarachnoid hemorrhage and might be inhibited by ring finger protein 144B. Moreover, parkin inhibition did not interfere with the mitophagic or apoptotic effects of autophagy-targeting chimera 4. These findings not only confirm that autophagy-targeting chimera 4 exerts neuroprotective effects by targeting mitophagy after subarachnoid hemorrhage, but also demonstrate competitive inhibition between ring finger protein 144B and parkin, leading to poor prognosis in the acute phase after subarachnoid hemorrhage.