Abstract
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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Acknowledgements
This work was supported by grants from NIH grant (RF1, AG051538) to K.Y. We thank ADRC at Emory University for human PD patients and healthy control samples. This study was supported in part by the Rodent Behavioral Core (RBC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities (P30NS055077). Further support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378, Hallym University Research Fund, 2021(HRF-202103-009), National Key R&D Program of China (2018YFC1314700), National Natural Science Foundation of China (81974196, 81873779) and Program of Shanghai Academic Research Leader (20XD1403400). Dr. Kecheng Lei was supported by grants from China Postdoctoral Science Foundation (2018M632168).
Author contributors
KY conceived the project, designed the experiments, analyzed the data and wrote the manuscript. EHA and KL designed and performed most of the experiments. SSK, XL prepared SH-SY5Y cells and assessed animal experiments. ZHW assisted with data analysis. WH and YTW provided important reagents and scientific discussion. LEM and LJ critically read the manuscript.
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Ahn, E.H., Lei, K., Kang, S.S. et al. Mitochondrial dysfunction triggers the pathogenesis of Parkinson’s disease in neuronal C/EBPβ transgenic mice. Mol Psychiatry 26, 7838–7850 (2021). https://doi.org/10.1038/s41380-021-01284-x
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DOI: https://doi.org/10.1038/s41380-021-01284-x
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