?-opioid receptor activation protects against Parkinson's disease-related mitochondrial dysfunction by enhancing PINK1/Parkin-dependent mitophagy.

ABSTRACT: Our previous studies have shown that the ?-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.

SUBMITTER: Xu Y 

PROVIDER: S-EPMC7803568 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature