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

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:12

Enthalten in:

Aging - 12(2020), 24 vom: 10. Nov., Seite 25035-25059

Sprache:

Englisch

Beteiligte Personen:

Xu, Yuan [VerfasserIn]
Zhi, Feng [VerfasserIn]
Mao, Jiahao [VerfasserIn]
Peng, Ya [VerfasserIn]
Shao, Naiyuan [VerfasserIn]
Balboni, Gianfranco [VerfasserIn]
Yang, Yilin [VerfasserIn]
Xia, Ying [VerfasserIn]

Links:

Volltext

Themen:

δ-Opioid receptor
1-Methyl-4-phenylpyridinium
11062-77-4
2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1H-benzimidazol-2-yl)(carboxymethyl)methylamide
Benzimidazoles
EC 2.3.2.27
EC 2.7.-
EC 2.7.11.1
Herbicides
Journal Article
Mitochondria
Oligopeptides
PINK1
PTEN-induced putative kinase
Parkin
Parkin protein
Protein Kinases
R865A5OY8J
Receptors, Opioid, delta
Research Support, Non-U.S. Gov't
Superoxides
Ubiquitin-Protein Ligases

Anmerkungen:

Date Completed 19.05.2021

Date Revised 19.05.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.18632/aging.103970

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM317652613