Journal
ACTA PHARMACOLOGICA SINICA
Volume 42, Issue 2, Pages 199-208Publisher
NATURE PUBL GROUP
DOI: 10.1038/s41401-020-0480-9
Keywords
garciesculenxanthone B; mitophagy; Parkin; PINK1; ischemia-reperfusion injury
Funding
- National Natural Science Foundation of China [81773951, 81303188]
- National Major Scientific and Technological Special Project for Significant New Drugs Development in 2018 [2019ZX09301140]
- Key-Area Research and Development Program of Guangdong Province [2020B1111110003]
- Three-Year Development Plan Project for Traditional Chinese Medicine [ZY(2018-2020)-CCCX-2001-02]
- NMRC [NMRC/CIRG/1430/2015]
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Mitophagy is a selective form of autophagy that removes damaged mitochondria via the autophagy-lysosome pathway. GeB, a natural compound, can promote the PINK1-Parkin-mediated mitophagy pathway, potentially protecting against I/R brain injury.
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 fromGarcinia 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 ofPINK1. 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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