Abstract
Mitophagy is a selective form of autophagy involving the removal of damaged mitochondria via the autophagy-lysosome pathway. PINK1-Parkin-mediated mitophagy is one of the most important mechanisms in cardiovascular disease, cerebral ischemia-reperfusion (I/R) injury, and neurodegenerative diseases. In this study we conducted an image-based screening in YFP-Parkin HeLa cells to discover new mitophagy regulators from natural xanthone compounds. We found that garciesculenxanthone B (GeB), a new xanthone compound from Garcinia esculenta, induced the formation of YFP-Parkin puncta, a well known mitophagy marker. Furthermore, treatment with GeB dose-dependently promoted the degradation of mitochondrial proteins Tom20, Tim23, and MFN1 in YFP-Parkin HeLa cells and SH-SY5Y cells. We revealed that GeB stabilized PINK1 and triggered Parkin translocation to the impaired mitochondria to induce mitophagy, and these effects were abolished by knockdown of PINK1. Finally, in vivo experiments demonstrated that GeB partially rescued ischemia-reperfusion-induced brain injury in mice. Taken together, our findings demonstrate that the natural compound GeB can promote the PINK1-Parkin-mediated mitophagy pathway, which may be implicated in protection against I/R brain injury.
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Acknowledgements
We are grateful to Richard J. Youle for providing the YFP-Parkin HeLa cells and plasmids. This work was supported by the National Natural Science Foundation of China (Nos. 81773951 and 81303188), the National Major Scientific and Technological Special Project for “Significant New Drugs Development” in 2018 (No. 2019ZX09301140), Key-Area Research and Development Program of Guangdong Province (2020B1111110003), the Three-Year Development Plan Project for Traditional Chinese Medicine (ZY(2018–2020)-CCCX-2001-02) to HXX and research grants from NMRC (NMRC/CIRG/1430/2015) to HMS.
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MW and GL performed the experiments and wrote the original draft; ZQZ, JY, and QX analyzed the data; YZL, HMS, and HXX designed the research and edited the paper; HZ and DZ extracted the compounds; LMW, HST, and HZ reviewed and edited the paper.
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Wu, M., Lu, G., Lao, Yz. et al. Garciesculenxanthone B induces PINK1-Parkin-mediated mitophagy and prevents ischemia-reperfusion brain injury in mice. Acta Pharmacol Sin 42, 199–208 (2021). https://doi.org/10.1038/s41401-020-0480-9
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DOI: https://doi.org/10.1038/s41401-020-0480-9
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