Gene therapy of yeast NDI1 on mitochondrial complex I dysfunction in rotenone-induced Parkinson’s disease models in vitro and vivo

作者：Hongzhi Li, Bohao Sun, Yuting Huang, Jing Zhang, Xuejing Xu, Yuqi Shen, Zhuo Chen, Jifeng Yang, Luxi Shen, Yongwu Hu, Haihua Gu · 发表于：Molecular Medicine · 年份：2022 · DOI：10.1186/s10020-022-00456-x · 被引用次数：35 · 研究领域：Sirtuins and Resveratrol in Medicine、Mitochondrial Function and Pathology、Endoplasmic Reticulum Stress and Disease

PURPOSE: Parkinson's disease (PD) is the second most common neurodegenerative disease without cure or effective treatment. This study explores whether the yeast internal NADH-quinone oxidoreductase (NDI1) can functionally replace the defective mammalian mitochondrial complex I, which may provide a gene therapy strategy for treating sporadic PD caused by mitochondrial complex I dysfunction. METHOD: Recombinant lentivirus expressing NDI1 was transduced into SH-SY5Y cells, or recombinant adeno-associated virus type 5 expressing NDI1 was transduced into the right substantia nigra pars compacta (SNpc) of mouse. PD cell and mouse models were established by rotenone treatment. The therapeutic effects of NDI1 on rotenone-induced PD models in vitro and vivo were assessed in neurobehavior, neuropathology, and mitochondrial functions, by using the apomorphine-induced rotation test, immunohistochemistry, immunofluorescence, western blot, complex I enzyme activity determination, oxygen consumption detection, ATP content determination and ROS measurement. RESULTS: NDI1 was expressed and localized in mitochondria in SH-SY5Y cells. NDI1 resisted rotenone-induced changes in cell morphology, loss of cell viability, accumulation of α-synuclein and pS129 α-synuclein, mitochondrial ROS production and mitochondria-mediated apoptosis. The basal and maximal oxygen consumption, mitochondrial coupling efficiency, basal and oligomycin-sensitive ATP and complex I activity in cell model were significantl...