Mitochondrial dysfunction triggers the pathogenesis of Parkinson's disease in neuronal C/EBPβ transgenic mice

• Published in: Molecular psychiatry Vol. 26; no. 12; pp. 7838 - 7850
• Main Authors: Ahn, Eun Hee, Lei, Kecheng, Kang, Seong Su, Wang, Zhi-Hao, Liu, Xia, Hong, Wei, Wang, Yu Tian, Edgington-Mitchell, Laura E, Jin, Lingjing, Ye, Keqiang
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2021
• Subjects: Animals; Atovaquone; Cell death; Constipation; Dopamine receptors; Dopaminergic Neurons - metabolism; Electron transport chain; Gene deletion; Lewy bodies; Mice; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Movement disorders; Neurodegenerative diseases; Oral administration; Oxidative phosphorylation; Oxidative Stress - physiology; Parkinson Disease - metabolism; Parkinson's disease; Pathogenesis; Phosphorylation; Respiration; Substantia nigra; Substantia Nigra - metabolism; Substantia Nigra - pathology; Succinate dehydrogenase; Transgenic animals; Transgenic mice
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-021-01284-x

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.