Regulation of mitochondrial dynamics and function by MT1 melatonin receptor in Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disease characterized by dopaminergic neurons loss and Lewy body presence in the substantia nigra. Abnormal mitochondrial function and accumulated alpha-synuclein (α-syn) are key etiology of PD. Melatonin type receptor 1 (MT1) regulates sleep upon activation by melatonin and is suggested to decrease in PD patients. However, the role of MT1 in PD pathogenesis remains elusive. In this study, we knocked down MT1 in SH-SY5Y neuroblastoma cells and found MT1 loss caused mitochondria dysfunction. Moreover, live cell imaging of MitoTracker staining and transmission electron microscope (TEM) proved that MT1 knockdown affected mitochondria morphology. The expression of mitochondria fission protein DRP1 was increased and the fusion protein OPA1, MFN1 and MFN2 was decreased. This is probably attributed to the declined phosphorylation of DRP1 at S637 by PKA and increased phosphorylation at S616 by ERK1/2. Moreover, MT1 knockdown also impaired mitophagy, manifested by declined PINK1 and Parkin. In a MPTP induced PD mouse model, MT1 deficiency altered the mitochondria fission through the same mechanism as in vitro but did not impair mitophagy, tyrosine hydroxylase (TH) expression and mice movement. However, MPTP induced autophagy inhibition was exacerbated in MT1 KO mice. Neuronal MT1 deficiency aggravated preformed fibrils (PFFs) induced autophagy inhibition and α-syn aggregation. Overexpression of MT1 reduced mitochondria fission, as well as increased LC3-II expression and decreased P62 accumulation to promote autophagy in HEK293T cells, thus mitigating the aggregation of α-syn. Autophagy flux indicated by mCherry-LC3-II-EGFP fluorescence was also enhanced after MT1 overexpression. Together, our study demonstrates the function of MT1 in mitochondria and autophagy, which sheds further light on PD prevention targeting MT1.