Morin exhibits a neuroprotective effect in MPTP-induced Parkinson's disease model via TFEB/AMPK-mediated mitophagy

Background: Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the world. Mitophagy has been implicated in PD etiology for decades and its pharmacological activation is recognized as a promising treatment strategy for PD. For mitophagy initiation, low mitochondrial membrane potential (ΔΨm) is essential. We identified a natural compound morin that could induce mitophagy without affecting ΔΨm. Morin is a flavonoid that can be isolated from fruits like mulberry. Purpose: To reveal the effect of morin on the PD mice model and their potential underlying molecular mechanism. Methods: Mitophagy process induced by morin in N2a cells meditation were measured using flow cytometry and immunofluorescence. JC-1 fluorescence dye used to detect the mitochondrial membrane potential (ΔΨm). The TFEB nuclear translocation were examined by immunofluorescence staining and western blot assay. The PD mice model was induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) intraperitoneal administration. Results: We found that morin also promoted nuclear translocation of the mitophagy regulator TFEB and activated the AMPK-ULK1 pathway. In MPTP-induced PD in vivo models, morin protected DA neurons from MPTP neurotoxicity and ameliorated behavioral deficit. Conclusion: Although morin was previously reported to be neuroprotective in PD, the detailed molecular mechanisms remain to be elucidated. For the first time, we report morin served as a novel and safe mitophagy enhancer underlying AMPK-ULK1 pathway and exhibited anti-Parkinsonian effects indicating its potential as a clinical drug for PD treatment.