Epileptiform Discharges Reduce Neuronal ATP Production by Inhibiting F0F1-ATP Synthase Activity via A Zinc-& alpha;2-Glycoprotein-Dependent Mechanism

作者全名："Liang, Yi; Zhao, Lili; Dai, Chengcheng; Liu, Guohui; Zhong, Yuke; Liu, Hang; Mo, Lijuan; Tan, Changhong; Liu, Xi; Chen, Lifen"

作者地址："[Liang, Yi; Zhao, Lili; Dai, Chengcheng; Liu, Guohui; Zhong, Yuke; Liu, Hang; Mo, Lijuan; Tan, Changhong; Liu, Xi; Chen, Lifen] Chongqing Med Univ, Affiliated Hosp 2, Dept Neurol, 74 Linjiang Rd, Chongqing 400010, Peoples R China"

通信作者："Liu, X; Chen, LF (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Neurol, 74 Linjiang Rd, Chongqing 400010, Peoples R China."

来源：MOLECULAR NEUROBIOLOGY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001032095600001

JCR分区：Q1

影响因子：4.6

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Epilepsy; Mitochondria; Energy supply; Enzyme activity; Oxidative phosphorylation

摘要："Neuronal energy metabolism dysfunction, especially adenosine triphosphate (ATP) supply decrease, is observed in epilepsy and associated with epileptogenesis and prognosis. Zinc-& alpha;2-glycoprotein (ZAG) is known as an important modulator of energy metabolism and involved in neuronal glucose metabolism, fatty acid metabolism, and ketogenesis impairment in seizures, but its effect on neuronal ATP synthesis in seizures and the specific mechanism are unclear. In this study, we verified the localization of ZAG in primary cultured neuronal mitochondria by using double-labeling immunofluorescence, immune electron microscopy, and western blot. ZAG level in neuronal mitochondria was modulated by lentiviruses and detected by western blot. The F0F1-ATP synthase activity, ATP level, and acetyl-CoA level were measured. The binding between ZAG and F0F1-ATP synthase was determined by coimmunoprecipitation. We found that both ZAG and F0F1-ATP synthase existed in neuronal mitochondria, and there was mutual binding between them. Epileptiform discharge-induced decrease of mitochondrial ZAG level was reversed by ZAG overexpression. Epileptiform discharge or ZAG knockdown decreased F0F1-ATP synthase activity and ATP level in neurons, which were reversed by ZAG overexpression, while overexpression of ZAG along only increased F0F1-ATP synthase activity but not increased ATP level. Meanwhile, neither epileptiform discharges nor changes of ZAG level can alter the acetyl-CoA level. Moreover, epileptiform discharge did not alter F0F1-ATP synthase level. In conclusion, epileptiform discharge-induced ZAG decrease in neuronal mitochondria is correlated to F0F1-ATP synthase activity inhibition, which may possibly lead to ATP supply impairments. ZAG may be a potential therapeutic target for treating neuronal energy metabolism dysfunction in seizures with further researches."

基金机构："National Natural Science Foundation of China [81771391, 82001367]; Natural Science Foundation of Chongqing [cstc2021jcyj-msxmX0180]; Kuanren Talent Program of The Second Affifiliated Hospital of Chongqing Medical University"

基金资助正文："This study is supported by the National Natural Science Foundation of China (grant number: 81771391, receiver: Lifen Chen; grant number: 82001367, receiver: Xi Liu), the Natural Science Foundation of Chongqing (grant number: cstc2021jcyj-msxmX0180, receiver: Xi Liu), and the Kuanren Talent Program of The Second Affifiliated Hospital of Chongqing Medical University (receiver: Xi Liu)."