Dysfunction of astrocytic glycophagy exacerbates reperfusion injury in ischemic stroke
Haiyun Guo,
Yumeng Li,
Shiquan Wang,
Yongheng Yang,
Tiantian Xu,
Jianshuai Zhao,
Jin Wang,
Wenqiang Zuo,
Pengju Wang,
Guangchao Zhao,
Huaning Wang,
Wugang Hou,
Hailong Dong,
Yanhui Cai
Affiliations
Haiyun Guo
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
Yumeng Li
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
Shiquan Wang
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
Yongheng Yang
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
Tiantian Xu
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
Jianshuai Zhao
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
Jin Wang
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
Wenqiang Zuo
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
Pengju Wang
The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
Guangchao Zhao
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
Huaning Wang
Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
Wugang Hou
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China; Corresponding author.
Hailong Dong
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China; Corresponding author.
Yanhui Cai
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China; Corresponding author. Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Glycophagy has evolved from an alternative glycogen degradation pathway into a multifaceted pivot to regulate cellular metabolic hemostasis in peripheral tissues. However, the pattern of glycophagy in the brain and its potential therapeutic impact on ischemic stroke remain unknown. Here, we observed that the dysfunction of astrocytic glycophagy was caused by the downregulation of the GABA type A receptor-associated protein like 1 (GABARAPL1) during reperfusion in ischemic stroke patients and mice. PI3K-Akt pathway activation is involved in driving GABARAPL1 downregulation during cerebral reperfusion. Moreover, glycophagy dysfunction-induced glucosamine deficiency suppresses the nuclear translocation of specificity protein 1 and TATA binding protein, the transcription factors for GABARAPL1, by decreasing their O-GlcNAcylation levels, and accordingly feedback inhibits GABARAPL1 in astrocytes during reperfusion. Restoring astrocytic glycophagy by overexpressing GABARAPL1 decreases DNA damage and oxidative injury in astrocytes and improves the survival of surrounding neurons during reperfusion. In addition, a hypocaloric diet in the acute phase after cerebral reperfusion can enhance astrocytic glycophagic flux and accelerate neurological recovery. In summary, glycophagy in the brain links autophagy, metabolism, and epigenetics together, and glycophagy dysfunction exacerbates reperfusion injury after ischemic stroke.
