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Myricetin stabilizes PINK1 to activate mitophagy and ameliorate metabolic dysfunction-associated steatotic liver
Weilong Xu1, Lijuan Nie2, Jing Cao3
1Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Background:
Myricetin, a bioactive flavonoid from Abelmoschus manihot, has demonstrated therapeutic potential for metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). However, its precise mechanisms, particularly concerning mitochondrial homeostasis, remain inadequately elucidated.
Objectives:
The present study evaluated the therapeutic efficacy of myricetin in alleviating hepatic steatosis, inflammation, fibrosis, and insulin resistance associated with MASLD/MASH, with a specific focus on unraveling the role of mitophagy regulation.
Methods:
MASLD and MASH models were established in mice using a high-fat diet (HFD) or a Gubra-Amylin NASH (GAN) diet, followed by myricetin treatment. Systemic metabolism, liver injury, histology, and insulin sensitivity were assessed. Transcriptomic profiling was performed to analyze metabolic pathways. Molecular docking, surface plasmon resonance (SPR), co-immunoprecipitation, and immunofluorescence were used to study the interaction between myricetin and PINK1 and its impact on PINK1/Parkin-mediated mitophagy. Finally, in vitro loss-of-function experiments using shPINK1 were conducted to validate the mechanism.
Results:
Myricetin significantly ameliorated hepatic steatosis, inflammation, fibrosis, and systemic insulin resistance in MASLD/MASH mice. Transcriptomics revealed enhanced fatty acid β-oxidation and mitochondrial function. Mechanistically, myricetin directly bound to PINK1, inhibiting its mitochondrial import through the TOM complex (TOM40) and subsequent cleavage by the PARL protease, thereby stabilizing PINK1 on the outer mitochondrial membrane. This stabilization activated PINK1/Parkin-dependent mitophagy, restoring mitochondrial integrity. Notably, the myricetin-mediated improvements in mitophagy and mitochondrial function were negated by PINK1 silencing.
Conclusion:
Myricetin mitigates MASLD/MASH progression by acting as a novel PINK1 stabilizer, augmenting PINK1/Parkin-dependent mitophagy to enhance mitochondrial quality. This study highlights myricetin as a potent intervention targeting mitochondria to combat metabolic liver diseases.
Insights
Myricetin, a natural compound, combats metabolic liver disease by stabilizing PINK1, enhancing mitophagy, and restoring mitochondrial function. This discovery offers a new therapeutic approach for fatty liver conditions.
Area of Science:
- Biochemistry
- Molecular Biology
- Hepatology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent significant health challenges.
- Myricetin, a flavonoid from Abelmoschus manihot, shows promise for MASLD/MASH, but its mechanisms, especially regarding mitochondrial health, require clarification.
Purpose of the Study:
- To evaluate myricetin's efficacy in treating hepatic steatosis, inflammation, fibrosis, and insulin resistance in MASLD/MASH.
- To elucidate the role of mitophagy regulation in myricetin's therapeutic effects.
Main Methods:
- MASLD/MASH mouse models were treated with myricetin.
- Systemic metabolism, liver injury, and insulin sensitivity were assessed.
- Molecular techniques including transcriptomics, molecular docking, SPR, co-immunoprecipitation, immunofluorescence, and in vitro loss-of-function studies were employed to investigate myricetin's interaction with PINK1 and mitophagy.
Main Results:
- Myricetin treatment significantly improved liver health and insulin sensitivity in MASLD/MASH mice.
- Transcriptomic analysis indicated enhanced fatty acid metabolism and mitochondrial function.
- Myricetin was found to stabilize PINK1 on the outer mitochondrial membrane, activating PINK1/Parkin-dependent mitophagy and restoring mitochondrial integrity.
Conclusions:
- Myricetin effectively mitigates MASLD/MASH progression by stabilizing PINK1 and enhancing mitophagy.
- This mechanism improves mitochondrial quality and function, positioning myricetin as a potential therapeutic agent for metabolic liver diseases.
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