Cargando…

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, th...

Descripción completa

Detalles Bibliográficos
Autores principales: Xu, Yuan, Zhi, Feng, Mao, Jiahao, Peng, Ya, Shao, Naiyuan, Balboni, Gianfranco, Yang, Yilin, Xia, Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803568/
https://www.ncbi.nlm.nih.gov/pubmed/33197884
http://dx.doi.org/10.18632/aging.103970
_version_ 1783635968066060288
author Xu, Yuan
Zhi, Feng
Mao, Jiahao
Peng, Ya
Shao, Naiyuan
Balboni, Gianfranco
Yang, Yilin
Xia, Ying
author_facet Xu, Yuan
Zhi, Feng
Mao, Jiahao
Peng, Ya
Shao, Naiyuan
Balboni, Gianfranco
Yang, Yilin
Xia, Ying
author_sort Xu, Yuan
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7803568
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Impact Journals
record_format MEDLINE/PubMed
spelling pubmed-78035682021-01-15 δ-opioid receptor activation protects against Parkinson’s disease-related mitochondrial dysfunction by enhancing PINK1/Parkin-dependent mitophagy Xu, Yuan Zhi, Feng Mao, Jiahao Peng, Ya Shao, Naiyuan Balboni, Gianfranco Yang, Yilin Xia, Ying Aging (Albany NY) Research Paper 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. Impact Journals 2020-11-10 /pmc/articles/PMC7803568/ /pubmed/33197884 http://dx.doi.org/10.18632/aging.103970 Text en Copyright: © 2020 Xu et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Xu, Yuan
Zhi, Feng
Mao, Jiahao
Peng, Ya
Shao, Naiyuan
Balboni, Gianfranco
Yang, Yilin
Xia, Ying
δ-opioid receptor activation protects against Parkinson’s disease-related mitochondrial dysfunction by enhancing PINK1/Parkin-dependent mitophagy
title δ-opioid receptor activation protects against Parkinson’s disease-related mitochondrial dysfunction by enhancing PINK1/Parkin-dependent mitophagy
title_full δ-opioid receptor activation protects against Parkinson’s disease-related mitochondrial dysfunction by enhancing PINK1/Parkin-dependent mitophagy
title_fullStr δ-opioid receptor activation protects against Parkinson’s disease-related mitochondrial dysfunction by enhancing PINK1/Parkin-dependent mitophagy
title_full_unstemmed δ-opioid receptor activation protects against Parkinson’s disease-related mitochondrial dysfunction by enhancing PINK1/Parkin-dependent mitophagy
title_short δ-opioid receptor activation protects against Parkinson’s disease-related mitochondrial dysfunction by enhancing PINK1/Parkin-dependent mitophagy
title_sort δ-opioid receptor activation protects against parkinson’s disease-related mitochondrial dysfunction by enhancing pink1/parkin-dependent mitophagy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803568/
https://www.ncbi.nlm.nih.gov/pubmed/33197884
http://dx.doi.org/10.18632/aging.103970
work_keys_str_mv AT xuyuan dopioidreceptoractivationprotectsagainstparkinsonsdiseaserelatedmitochondrialdysfunctionbyenhancingpink1parkindependentmitophagy
AT zhifeng dopioidreceptoractivationprotectsagainstparkinsonsdiseaserelatedmitochondrialdysfunctionbyenhancingpink1parkindependentmitophagy
AT maojiahao dopioidreceptoractivationprotectsagainstparkinsonsdiseaserelatedmitochondrialdysfunctionbyenhancingpink1parkindependentmitophagy
AT pengya dopioidreceptoractivationprotectsagainstparkinsonsdiseaserelatedmitochondrialdysfunctionbyenhancingpink1parkindependentmitophagy
AT shaonaiyuan dopioidreceptoractivationprotectsagainstparkinsonsdiseaserelatedmitochondrialdysfunctionbyenhancingpink1parkindependentmitophagy
AT balbonigianfranco dopioidreceptoractivationprotectsagainstparkinsonsdiseaserelatedmitochondrialdysfunctionbyenhancingpink1parkindependentmitophagy
AT yangyilin dopioidreceptoractivationprotectsagainstparkinsonsdiseaserelatedmitochondrialdysfunctionbyenhancingpink1parkindependentmitophagy
AT xiaying dopioidreceptoractivationprotectsagainstparkinsonsdiseaserelatedmitochondrialdysfunctionbyenhancingpink1parkindependentmitophagy