Neural Regeneration Research ›› 2024, Vol. 19 ›› Issue (1): 196-204.doi: 10.4103/1673-5374.378010

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

Xiang Chen1, #, Yuwan Lin1, #, Zhiling Zhang1, Yuting Tang1, Panghai Ye1, Wei Dai1, Wenlong Zhang1, Hanqun Liu1, Guoyou Peng1, Shuxuan Huang2, Jiewen Qiu1, Wenyuan Guo1, Xiaoqin Zhu3, Zhuohua Wu1, Yaoyun Kuang1, *, Pingyi Xu1, *, Miaomiao Zhou1, 4, *   

  1. 1Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China; 2Department of Neurology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region, China; 3School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong Province, China; 4Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • Online:2024-01-15 Published:2023-08-02
  • Contact: Miaomiao Zhou, MD, PhD, zhouzhou8601@126.com; Pingyi Xu, MD, PhD, pingyixu@sina.com; Yaoyun Kuang, MD, PhD, Kuangyaoyun@163.com.
  • Supported by:
    This study was 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); and Science and Technology Planning Project of Guangzhou, Nos. 202102020029 (to XC), 202102010010 (to PX).

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Abstract: Mitochondrial dysfunction is a significant pathological alteration that occurs in Parkinson’s disease (PD), and the Thr61Ile (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. F1F0-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 T61I-mutant CHCHD2 in regulating F1F0-ATPase activity in Parkinson’s disease, as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1F0-ATPase activity, remain unclear. Therefore, in this study, we expressed WT CHCHD2 and T61I-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, overexpression of WT CHCHD2 promoted F1F0-ATPase assembly, while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1F0-ATPase assembly. In addition, mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1F0-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.

Key words: 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