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?-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

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

Xu Yuan Y Zhi Feng F Mao Jiahao J Peng Ya Y Shao Naiyuan N Balboni Gianfranco G Yang Yilin Y Xia Ying Y

Aging 20201110 24

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+ ...[more]

PMID: 33197884

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Project description:BackgroundMechanical ventilation (MV) often leads to ventilation-induced diaphragm dysfunction (VIDD). Although the development of this disorder had been linked to oxidative stress, mitochondrial energy deficiency, autophagy activation, and apoptosis in the diaphragm, it remains unclear whether the activation of mitophagy can induce VIDD. With our research, our endeavor is to uncover whether PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy affects the MV-caused diaphragmatic dysfunction.MethodsSprague-Dawley rats were subjected to MV treatment for 6 h (MV-6h), 12 h (MV-12h), or 24 h (MV-24h). Post MV, the diaphragm muscle compound action potential (CMAP) and cross-sectional areas (CSAs) of the diaphragm of these rats were measured. The levels of proteins of interest were examined to assess muscle health, mitochondrial dynamics, and mitophagy in the diaphragm. The co-localization of PINK1 with the mitochondrial protein marker tom20 was examined, as well as transmission electron microscopy analysis to detect changes in diaphragm mitochondrial ultrastructure.ResultsMV-12h and MV-24h treatments resulted in a decrease in CSA of diaphragm and CMAP amplitude. In addition, the expressions of F-box (MFAbx), muscle-specific ring finger 1 (MURF1), PINK1, and p62 were elevated in rats treated with MV for 12 h and 24 h, while mfn2 expression was reduced. Rats following MV-24h treatment displayed an increase in mitochondrial dynamic protein (Drp1) and Parkin expression and microtubule-associated protein 1 light chain 3/1 (LC3II/I) ratio. Moreover, decreased SOD and GSH activity and membrane potential were observed after MV-12h and MV-24h treatment, while H2O2 activity increased after MV-24h treatment. In addition, a strong co-localization between PINK1 and tom20 was identified.ConclusionThese results reveal that MV leads to various changes in mitochondrial dynamics and significantly increases the mitophagy levels, which subsequently cause the variation in diaphragmatic function and muscle atrophy, indicating that mitophagy could be one of the possible mechanisms by which MV induces diaphragmatic dysfunction.The reviews of this paper are available via the supplemental material section.

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

Publications

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

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