Frataxin-Mediated PINK1-Parkin-Dependent Mitophagy in Hepatic Steatosis: The Protective Effects of Quercetin.

Scope: Naturally occurring quercetin has been found to induce mitophagy and prevent nonalcoholic fatty liver disease (NAFLD). However, it still remains elusive whether frataxin upregulation by quercetin contributes to the beneficial effect through mitophagy or not. Methods and results: Adult male C57BL/J mice were fed a high-fat diet (HFD, 60% of energy from fat) with quercetin (100 mg kg(-1) body weight) or not for 10 weeks. Quercetin alleviated HFD-induced histopathological changes, disorders of lipid metabolism, and mitochondrial damage. Moreover, quercetin blocked mitophagy suppression by HFD based on the increased LC3II, PTEN-induced putative kinase 1 (PINK1) and Beclin1 expressions, as well as decreased p62 levels. Quercetin also improved the Parkin translocation to mitochondria confirmed by immunofluorescence. Specifically, frataxin was lowered in the liver of HFD-fed mice or HepG2 cell incubated with oleate/palmitate but restored by quercetin, and quercetin's regulation of frataxin may depend on p53. Furthermore, lentivirus-mediated stable knockdown of frataxin in HepG2 inhibited PINK1-Parkin-associated mitophagy and resulted in lipid accumulation. Frataxin was further decreased by free fatty acids in knockdown cells concomitantly with depressed PINK1-Parkin-associated mitophagy, which was partially normalized by quercetin. Conclusion: Quercetin alleviated hepatic steatosis by enhancing frataxin-mediated PINK1/Parkin-dependent mitophagy, highlighting a promising preventive strategy and mechanism for NAFLD by quercetin.