β-arrestin1 regulates astrocytic reactivity via Drp1-dependent mitochondrial fission: implications in postoperative delirium

Journal of Neuroinflammation

Research

Hua Li¹  Weidong Liang²  Xifeng Wang³  Pengcheng Yi⁴  Yao Dong⁴  Qingcui Zheng⁴  Wen Yu⁴  Fan Xiao⁴  Yanhong Xiong⁴  Lieliang Zhang⁴  Hailin Liu⁴  Fuzhou Hua⁴  Yue Lin⁴  Jun Ying⁴  Hong Zhu⁵  Lanran Fang⁶ 

[1] Department of Anesthesiology, First People’s Hospital of Yihuang County, 344400, Fuzhou, Jiangxi, People’s Republic of China;Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, 341000, Ganzhou, Jiangxi, People’s Republic of China;Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, 17# Yong Wai Zheng Street, 330006, Nanchang, Jiangxi, People’s Republic of China;Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, 1# Minde Road, 330006, Nanchang, Jiangxi, People’s Republic of China;Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, 330006, Nanchang, Jiangxi, People’s Republic of China;Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, 330006, Nanchang, Jiangxi, People’s Republic of China;Department of Statistics, Jiangxi University of Finance and Economics, 330013, Nanchang, Jiangxi, People’s Republic of China;

关键词: Postoperative delirium;    Neuroinflammation;    Astrocytes;    β-Arrestins;    Mitochondrial fission;   

DOI  :  10.1186/s12974-023-02794-x

 received in 2023-01-07, accepted in 2023-04-24,  发布年份 2023

来源: Springer

【 摘 要 】

Postoperative delirium (POD) is a frequent and debilitating complication, especially amongst high risk procedures, such as orthopedic surgery. This kind of neurocognitive disorder negatively affects cognitive domains, such as memory, awareness, attention, and concentration after surgery; however, its pathophysiology remains unknown. Multiple lines of evidence supporting the occurrence of inflammatory events have come forward from studies in human patients’ brain and bio-fluids (CSF and serum), as well as in animal models for POD. β-arrestins are downstream molecules of guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). As versatile proteins, they regulate numerous pathophysiological processes of inflammatory diseases by scaffolding with inflammation-linked partners. Here we report that β-arrestin1, one type of β-arrestins, decreases significantly in the reactive astrocytes of a mouse model for POD. Using β-arrestin1 knockout (KO) mice, we find aggravating effect of β-arrestin1 deficiency on the cognitive dysfunctions and inflammatory phenotype of astrocytes in POD model mice. We conduct the in vitro experiments to investigate the regulatory roles of β-arrestin1 and demonstrate that β-arrestin1 in astrocytes interacts with the dynamin-related protein 1 (Drp1) to regulate mitochondrial fusion/fission process. β-arrestin1 deletion cancels the combination of β-arrestin1 and cellular Drp1, thus promoting the translocation of Drp1 to mitochondrial membrane to provoke the mitochondrial fragments and the subsequent mitochondrial malfunctions. Using β-arrestin1-biased agonist, cognitive dysfunctions of POD mice and pathogenic activation of astrocytes in the POD-linked brain region are reduced. We, therefore, conclude that β-arrestin1 is a promising target for the understanding of POD pathology and development of POD therapeutics.

【 授权许可】

CC BY   
© The Author(s) 2023

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