CHCHD2 Thr61Ile mutation impairs F1F0-ATPase assembly in in vitro and in vivo models of Parkinson's disease  

作　　者：Xiang Chen Yuwan Lin Zhiling Zhang Yuting Tang Panghai Ye Wei Dai Wenlong Zhang Hanqun Liu Guoyou Peng Shuxuan Huang Jiewen Qiu Wenyuan Guo Xiaoqin Zhu Zhuohua Wu Yaoyun Kuang Pingyi Xu Miaomiao Zhou 

机构地区：[1]Department of Neurology,The First Affiliated Hospital of Guangzhou Medical University,Guangzhou,Guangdong Province,China [2]Department of Neurology,The People’s Hospital of Guangxi Zhuang Autonomous Region,Nanning,Guangxi Zhuang Autonomous Region,China [3]School of Basic Medical Sciences,Guangzhou Medical University,Guangzhou,Guangdong Province,China [4]Department of Neurology,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,China

出　　处：《Neural Regeneration Research》2024年第1期196-204,共9页中国神经再生研究（英文版）

基　　金：supported by the National Natural Science Foundation of China(Youth Program),No.81901282(to XC);the National Natural Science Foundation of China,Nos.81401416(to PX),81870992(to PX),81870856(to XC and MZ);Guangdong Basic and Applied Basic Research Foundation the Science Foundation,No.2019A1515011189(to XC);Central Government Guiding Local Science and Technology Development Projects,No.ZYYD2022C17(to PX);Key Project of Guangzhou Health Commission,No.2019-ZD-09(to PX);Science and Technology Planning Project of Guangzhou,Nos.202102020029(to XC),202102010010(to PX)。

摘　　要：Mitochondrial dysfunction is a significant pathological alte ration that occurs in Parkinson's disease(PD),and the Thr61lle(T61I)mutation in coiled-coil helix coiled-coil helix domain containing 2(CHCHD2),a crucial mitochondrial protein,has been reported to cause Parkinson's disease.FIFO-ATPase participates in the synthesis of cellular adenosine triphosphate(ATP)and plays a central role in mitochondrial energy metabolism.However,the specific roles of wild-type(WT)CHCHD2 and T611-mutant CHCHD2 in regulating F1FO-ATPase activity in Parkinson's disease,as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1FO-ATPase activity,remain unclea r.Therefore,in this study,we expressed WT CHCHD2 and T61l-mutant CHCHD2 in an MPP^(+)-induced SH-SY5Y cell model of PD.We found that CHCHD2 protected mitochondria from developing MPP^(+)-induced dysfunction.Under normal conditions,ove rexpression of WT CHCHD2 promoted F1FO-ATPase assembly,while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1FO-ATPase assembly.In addition,mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1FO-ATPase.Three weeks after transfection with AAV-CHCHD2 T61I,we intraperitoneally injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into mice to establish an animal model of chronic Parkinson's disease and found that exogenous expression of the mutant protein worsened the behavioral deficits and dopaminergic neurodegeneration seen in this model.These findings suggest that WT CHCHD2 can alleviate mitochondrial dysfunction in PD by maintaining F1F0-ATPase structure and function.

关 键 词：ATP synthase(F1F0-ATPase) coiled-coil helix coiled-coil helix domain containing 2 dopaminergic neuron mitochondrial dysfunction NEURODEGENERATION oligomycin sensitivity-conferring protein Parkinson's disease T61I mutation tyrosine hydroxylase 

分 类 号：R742.5[医药卫生—神经病学与精神病学]