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 |
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Erscheinungsjahr: |
2020 |
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Erschienen: |
2020 |
Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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Enthalten in: |
Aging - 12(2020), 24 vom: 10. Nov., Seite 25035-25059 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Xu, Yuan [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 19.05.2021 Date Revised 19.05.2021 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.18632/aging.103970 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM317652613 |
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245 | 1 | 0 | |a δ-opioid receptor activation protects against Parkinson's disease-related mitochondrial dysfunction by enhancing PINK1/Parkin-dependent mitophagy |
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520 | |a 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 | ||
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650 | 4 | |a PINK1 | |
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650 | 4 | |a δ-Opioid receptor | |
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700 | 1 | |a Balboni, Gianfranco |e verfasserin |4 aut | |
700 | 1 | |a Yang, Yilin |e verfasserin |4 aut | |
700 | 1 | |a Xia, Ying |e verfasserin |4 aut | |
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