黑质
线粒体呼吸链
呼吸链
发病机制
生物
线粒体
转基因小鼠
帕金森病
多巴胺能
细胞生物学
转基因
内科学
神经科学
多巴胺
医学
免疫学
生物化学
疾病
基因
作者
Eun Hee Ahn,Kecheng Lei,Seong Su Kang,Zhi-Hao Wang,Xia Liu,Wei Hong,Yu Tian Wang,Laura E. Edgington‐Mitchell,Lingjing Jin,Keqiang Ye
标识
DOI:10.1038/s41380-021-01284-x
摘要
Respiratory chain complex I deficiency elicits mitochondrial dysfunction and reactive oxidative species (ROS), which plays a crucial role in Parkinson's disease (PD) pathogenesis. However, it remains unclear whether the impairment in other complexes in the mitochondrial oxidative phosphorylation chain is also sufficient to trigger PD onset. Here we show that inhibition of Complex II or III in the electron transport chain (ETC) induces the motor disorder and PD pathologies in neuronal Thy1-C/EBPβ transgenic mice. Through a cell-based screening of mitochondrial respiratory chain inhibitors, we identified TTFA (complex II inhibitor) and Atovaquone (complex III inhibitor), which robustly block the oxidative phosphorylation functions, strongly escalate ROS, and activate C/EBPβ/AEP pathway that triggers dopaminergic neuronal cell death. Oral administration of these inhibitors to Thy1-C/EBPβ mice elicits constipation and motor defects, associated with Lewy body-like inclusions. Deletion of SDHD (Succinate dehydrogenase) gene from the complex II in the Substantia Nigra of Thy1-C/EBPβ mice triggers ROS and PD pathologies, resulting in motor disorders. Hence, our findings demonstrate that mitochondrial ETC inactivation triggers PD pathogenesis via activating C/EBPβ/AEP pathway.
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