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Garciesculenxanthone B induces PINK1-Parkin-mediated mitophagy and prevents ischemia-reperfusion brain injury in mice

Authors: Man Wu1,2, Guang Lu3, Yuan-zhi Lao2, Hong Zhang2, Dan Zheng2, Zhao-qing Zheng2, Juan Yi4, Qian Xiang2, Li-ming Wang3, Hong-sheng Tan2, Hua Zhou1, Han-ming Shen3,5, Hong-xi Xu1
1 Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
2 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
3 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
4 School of Basic Medical Science, Lanzhou University, Lanzhou 730000, China
5 Faculty of Health Sciences, University of Macau, Macau, China
Correspondence to: Han-ming Shen: phsshm@nus.edu.sg, Hong-xi Xu: xuhongxi88@gmail.com,
DOI: 10.1038/s41401-020-0480-9
Received: 16 February 2020
Accepted: 7 July 2020
Advance online: 5 August 2020

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.
Keywords: garciesculenxanthone B; mitophagy; Parkin; PINK1; ischemia-reperfusion injury

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