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

• Published in: Acta pharmacologica Sinica Vol. 42; no. 2; pp. 199 - 208
• Main Authors: Wu, Man, Lu, Guang, Lao, Yuan-zhi, Zhang, Hong, Zheng, Dan, Zheng, Zhao-qing, Yi, Juan, Xiang, Qian, Wang, Li-ming, Tan, Hong-sheng, Zhou, Hua, Shen, Han-ming, Xu, Hong-xi
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01-02-2021; Nature Publishing Group
• Subjects: Animals; Autophagy; Biomedical and Life Sciences; Biomedicine; Brain injury; Brain Ischemia - prevention & control; Cardiovascular diseases; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Garcinia - chemistry; Gene Knockdown Techniques; HeLa Cells; Humans; Immunology; Internal Medicine; Ischemia; Male; Medical Microbiology; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Mitophagy; Mitophagy - drug effects; Neurodegenerative diseases; Parkin protein; Phagocytosis; Pharmacology/Toxicology; Protein Kinases - genetics; Protein Kinases - metabolism; PTEN-induced putative kinase; Reperfusion; Reperfusion Injury - prevention & control; Traumatic brain injury; Ubiquitin-Protein Ligases - metabolism; Vaccine; Xanthones - administration & dosage; Xanthones - isolation & purification; Xanthones - pharmacology; ischemia-reperfusion injury; mitophagy; PINK1; garciesculenxanthone B; Parkin
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-020-0480-9

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.