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Dendrobium nobile Lindl. alkaloids alleviate Mn-induced neurotoxicity via PINK1/Parkin-mediated mitophagy in PC12 cells.

ABSTRACT: Modern pharmacological studies have demonstrated that Dendrobium nobile Lindl. Alkaloids (DNLA), the main active ingredients of Dendrobium nobile, is valuable as an anti-aging and neuroprotective herbal medicine. The present study was designed to determine whether DNLA confers protective function over neurotoxicant manganese (Mn)-induced cytotoxicity and the mechanism involved. Our results showed that pretreatment of PC12 cells with DNLA alleviated cell toxicity induced by Mn and improved mitochondrial respiratory capacity and oxidative status. Mn treatment increased apoptotic cell death along with a marked increase in the protein expression of Bax and a decrease in the expression of Bcl-2 protein, all of which were noticeably reversed by DNLA. Furthermore, DNLA significantly abolished the decrease in protein levels of both PINK1 and Parkin, and mitigated the increased expression of autophagy marker LC3-II and accumulation of p62 caused by Mn. These results demonstrate that DNLA inhibits Mn induced cytotoxicity, which may be mediated through modulating PINK1/Parkin-mediated autophagic flux and improving mitochondrial function.

SUBMITTER: Fu X

PROVIDER: S-EPMC8047462 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Dendrobium nobile Lindl. alkaloids alleviate Mn-induced neurotoxicity via PINK1/Parkin-mediated mitophagy in PC12 cells.

Fu Xiaolong X Chen Shu S Wang Xueting X Shen Yanhua Y Zeng Ru R Wu Qin Q Lu Yuanfu Y Shi Jingshan J Zhou Shaoyu S

Biochemistry and biophysics reports 20210402

Modern pharmacological studies have demonstrated that Dendrobium nobile Lindl. Alkaloids (DNLA), the main active ingredients of Dendrobium nobile, is valuable as an anti-aging and neuroprotective herbal medicine. The present study was designed to determine whether DNLA confers protective function over neurotoxicant manganese (Mn)-induced cytotoxicity and the mechanism involved. Our results showed that pretreatment of PC12 cells with DNLA alleviated cell toxicity induced by Mn and i ...[more]

PMID: 33889759

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Project description:MitoNEET, a mitochondrial outer membrane protein containing the Asn-Glu-Glu-Thr (NEET) sequence, controls the formation of intermitochondrial junctions and confers autophagy resistance. Moreover, mitoNEET as a mitochondrial substrate undergoes ubiquitination by activated Parkin during the initiation of mitophagy. Therefore, mitoNEET is linked to the regulation of autophagy and mitophagy. Mitophagy is the selective removal of the damaged or unnecessary mitochondria, which is crucial to sustaining mitochondrial quality control. In numerous human diseases, the accumulation of damaged mitochondria by impaired mitophagy has been observed. However, the therapeutic strategy targeting of mitoNEET as a mitophagy-enhancing mediator requires further research. Herein, we confirmed that mitophagy is indeed activated by mitoNEET inhibition. CCCP (carbonyl cyanide m-chlorophenyl hydrazone), which leads to mitochondrial depolarization, induces mitochondrial dysfunction and superoxide production. This, in turn, contributes to the induction of mitophagy; mitoNEET protein levels were initially increased before an increase in LC3-Ⅱ protein following CCCP treatment. Pharmacological inhibition of mitoNEET using mitoNEET Ligand-1 (NL-1) promoted accumulation of Pink1 and Parkin, which are mitophagy-associated proteins, and activation of mitochondria-lysosome crosstalk, in comparison to CCCP alone. Inhibition of mitoNEET using NL-1, or mitoNEET shRNA transfected into RAW264.7 cells, abrogated CCCP-induced ROS and mitochondrial cell death; additionally, it activated the expression of PGC-1α and SOD2, regulators of oxidative metabolism. In particular, the increase in PGC-1α, which is a major regulator of mitochondrial biogenesis, promotes mitochondrial quality control. These results indicated that mitoNEET is a potential therapeutic target in numerous human diseases to enhance mitophagy and protect cells by maintaining a network of healthy mitochondria. [BMB Reports 2022; 55(7): 354-359].

Dataset Information

Dendrobium nobile Lindl. alkaloids alleviate Mn-induced neurotoxicity via PINK1/Parkin-mediated mitophagy in PC12 cells.

Publications

<i>Dendrobium nobile</i> Lindl. alkaloids alleviate Mn-induced neurotoxicity via PINK1/Parkin-mediated mitophagy in PC12 cells.

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