Research Paper Volume 12, Issue 24 pp 25035—25059
δ-opioid receptor activation protects against Parkinson’s disease-related mitochondrial dysfunction by enhancing PINK1/Parkin-dependent mitophagy
- 1 Department of Neurosurgery, The First People’s Hospital of Changzhou, Changzhou, Jiangsu, China
- 2 Modern Medical Research Center, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- 3 Department of Life and Environment Sciences, University of Cagliari, Cagliari, Italy
- 4 Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Department of Aeronautics and Astronautics, Fudan University, Shanghai, China
Received: February 5, 2020 Accepted: July 31, 2020 Published: November 10, 2020
https://doi.org/10.18632/aging.103970How to Cite
Abstract
Our previous studies have shown that the δ-opioid receptor (DOR) is an important neuroprotector via the regulation of PTEN-induced kinase 1 (PINK1), a mitochondria-related molecule, under hypoxic and MPP+ insults. Since mitochondrial dysfunctions are observed in both hypoxia and MPP+ insults, this study further investigated whether DOR is cytoprotective against these insults by targeting mitochondria. Through comparing DOR-induced responses to hypoxia versus MPP+-induced parkinsonian insult in PC12 cells, we found that both hypoxia and MPP+ caused a collapse of mitochondrial membrane potential and severe mitochondrial dysfunction. In sharp contrast to its inappreciable effect on mitochondria in hypoxic conditions, DOR activation with UFP-512, a specific agonist, significantly attenuated the MPP+-induced mitochondrial injury. Mechanistically, DOR activation effectively upregulated PINK1 expression and promoted Parkin’s mitochondrial translocation and modification, thus enhancing the PINK1-Parkin mediated mitophagy. Either PINK1 knockdown or DOR knockdown largely interfered with the DOR-mediated mitoprotection in MPP+ conditions. Moreover, there was a major difference between hypoxia versus MPP+ in terms of the regulation of mitophagy with hypoxia-induced mitophagy being independent from DOR-PINK1 signaling. Taken together, our novel data suggest that DOR activation is neuroprotective against parkinsonian injury by specifically promoting mitophagy in a PINK1-dependent pathway and thus attenuating mitochondrial damage.