Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (9): 4331-4341.doi: 10.4103/NRR.NRR-D-25-00705

Previous Articles     Next Articles

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

Yongzhi Zhang1, Jianqiao Li1, Qi Sun1, Peichun Zhou2, Pei Wu1, Zhiyong Ji1, *, Yuchen Li1, *, Huaizhang Shi1, *   

  1. 1Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; 
    2Harbin Medical University, Harbin, Heilongjiang Province, China
  • Online:2026-09-15 Published:2026-05-21
  • Contact: Huaizhang Shi, PhD, huaizhangshi@163.com; Yuchen Li, PhD, liyuchen8999@163.com; Zhiyong Ji, PhD, jizhiyong1980@163.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 82071309 (to HS); the Key Research and Development Plan Project of Heilongjiang Province, No. 2022ZX06C03 (to HS); the Postgraduate Research & Practice Innovation Program of Harbin Medical University, No. YJSCX2023-62HYD (to YZ); the Scientific Innovation Foundation of the First Affiliated Hospital of Harbin Medical University, No. 2025M09 (to ZJ); the Outstanding Youth Project of the Natural Science Foundation of Heilongjiang Province, No. YQ2023H008 (to YL); the General Project of the China Postdoctoral Science Foundation Project, No. 2021MD703829 (to YL); the General Project of the Heilongjiang Provincial Postdoctoral Science Foundation Project, No. LBH-Z20169 (to YL); the Young Talents Program of the First Affiliated Hospital of Harbin Medical University, No. 2021Y10 (to YL); and the Natural Science Foundation of Heilongjiang Province, No. PL2024H055 (to PW).

PDF

1

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.

Key words: apoptosis, autophagy, brain injury, mitochondrial membrane potential, mitochondrion, mitophagy, neurons, stroke, subarachnoid hemorrhage, ubiquitin