Objective: This study aimed to explore the role of melatonin receptor 1 (MT1) in improving mitochondrial dysfunction in MPP⁺/MPTP-induced PD models and to clarify the underlying mechanism.

Background: Mitochondrial dysfunction, particularly complex I (CI) inhibition, plays a crucial role in PD development. The Senp1-Sirt3 signaling pathway is a well-established regulator of mitochondrial metabolic stress. Melatonin provides various neuroprotective benefits, and its specific membrane receptor, MT1, is widely present in the central nervous system. However, direct evidence linking MT1 to the regulation of mitochondrial function in PD remains limited.

Method: MT1-knockdown SH-SY5Y cells were used to assess mitochondrial membrane potential (MMP), morphology, and ATP levels, while MT1 receptor inhibition was employed to evaluate ROS production. Mitochondria complex I activity measurement using assay kits. Administration of the highly selective MT1 agonist Ramelteon (RMT) was performed to evaluate mitochondrial function, Senp1 protein levels, and post-translational modifications of Sirt3. In vivo, mice received daily RMT pretreatment for one week prior to acute MPTP modeling. Dopaminergic neuron (DAN) survival was assessed by immunofluorescence and western blot, and motor function was evaluated using open field and pole tests.

Results: MT1 knockdown resulted in decreased MMP, lower ATP levels, and mitochondrial fragmentation, whereas MT1 inhibition increased ROS levels. MT1 deficiency exacerbated the inhibition of complex I activity caused by MPP⁺ and MPTP. In vitro, RMT treatment significantly restored MMP, increased ATP levels, and reduced ROS production compared to the MPP⁺ alone group. In vivo, MPTP-treated mice receiving RMT showed a significant increase in the number of DANs compared to the MPTP-only group, along with improved motor function, as shown by greater travel distance and velocity in the open field test and decreased latency in the pole test. RMT treatment also reversed the MPP⁺-induced decrease in mitochondrial Senp1 protein levels and the increases in mitochondrial protein acetylation and in the acetylation of the CI subunit NDUFS3.

Conclusion: MT1 activation sustains CI activity and preserves mitochondrial function through the Senp1-Sirt3 signaling axis, thereby protecting DANs and reducing motor deficits in MPTP-induced PD mice.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/activation-of-the-mt1-receptor-ameliorates-mitochondrial-dysfunction-in-mpp-mptp-induced-parkinsons-disease/