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SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway

SIRT3 is a class III histone deacetylase that modulates energy metabolism, genomic stability and stress resistance. It has been implicated as a potential therapeutic target in a variety of neurodegenerative diseases, including Parkinson’s disease (PD). Our previous study demonstrates that SIRT3 had...

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Autores principales: Zhang, Meng, Deng, Yong-Ning, Zhang, Jing-Yi, Liu, Jie, Li, Yan-Bo, Su, Hua, Qu, Qiu-Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: JKL International LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963348/
https://www.ncbi.nlm.nih.gov/pubmed/29896416
http://dx.doi.org/10.14336/AD.2017.0517
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author Zhang, Meng
Deng, Yong-Ning
Zhang, Jing-Yi
Liu, Jie
Li, Yan-Bo
Su, Hua
Qu, Qiu-Min
author_facet Zhang, Meng
Deng, Yong-Ning
Zhang, Jing-Yi
Liu, Jie
Li, Yan-Bo
Su, Hua
Qu, Qiu-Min
author_sort Zhang, Meng
collection PubMed
description SIRT3 is a class III histone deacetylase that modulates energy metabolism, genomic stability and stress resistance. It has been implicated as a potential therapeutic target in a variety of neurodegenerative diseases, including Parkinson’s disease (PD). Our previous study demonstrates that SIRT3 had a neuroprotective effect on a rotenone-induced PD cell model, however, the exact mechanism is unknown. In this study, we investigated the underlying mechanism. We established a SIRT3 stable overexpression cell line using lentivirus infection in SH-SY5Y cells. Then, a PD cell model was established using rotenone. Our data demonstrate that overexpression of SIRT3 increased the level of the autophagy markers LC3 II and Beclin 1. After addition of the autophagy inhibitor 3-MA, the protective effect of SIRT3 diminished: the cell viability decreased, while the apoptosis rate increased; α-synuclein accumulation enhanced; ROS production increased; antioxidants levels, including SOD and GSH, decreased; and MMP collapsed. These results reveal that SIRT3 has neuroprotective effects on a PD cell model by up-regulating autophagy. Furthermore, SIRT3 overexpression also promoted LKB1 phosphorylation, followed by activation of AMPK and decreased phosphorylation of mTOR. These results suggest that the LKB1-AMPK-mTOR pathway has a role in induction of autophagy. Together, our findings indicate a novel mechanism by which SIRT3 protects a rotenone-induced PD cell model through the regulation of autophagy, which, in part, is mediated by activation of the LKB1-AMPK-mTOR pathway.
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spelling pubmed-59633482018-06-12 SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway Zhang, Meng Deng, Yong-Ning Zhang, Jing-Yi Liu, Jie Li, Yan-Bo Su, Hua Qu, Qiu-Min Aging Dis Orginal Article SIRT3 is a class III histone deacetylase that modulates energy metabolism, genomic stability and stress resistance. It has been implicated as a potential therapeutic target in a variety of neurodegenerative diseases, including Parkinson’s disease (PD). Our previous study demonstrates that SIRT3 had a neuroprotective effect on a rotenone-induced PD cell model, however, the exact mechanism is unknown. In this study, we investigated the underlying mechanism. We established a SIRT3 stable overexpression cell line using lentivirus infection in SH-SY5Y cells. Then, a PD cell model was established using rotenone. Our data demonstrate that overexpression of SIRT3 increased the level of the autophagy markers LC3 II and Beclin 1. After addition of the autophagy inhibitor 3-MA, the protective effect of SIRT3 diminished: the cell viability decreased, while the apoptosis rate increased; α-synuclein accumulation enhanced; ROS production increased; antioxidants levels, including SOD and GSH, decreased; and MMP collapsed. These results reveal that SIRT3 has neuroprotective effects on a PD cell model by up-regulating autophagy. Furthermore, SIRT3 overexpression also promoted LKB1 phosphorylation, followed by activation of AMPK and decreased phosphorylation of mTOR. These results suggest that the LKB1-AMPK-mTOR pathway has a role in induction of autophagy. Together, our findings indicate a novel mechanism by which SIRT3 protects a rotenone-induced PD cell model through the regulation of autophagy, which, in part, is mediated by activation of the LKB1-AMPK-mTOR pathway. JKL International LLC 2018-04-01 /pmc/articles/PMC5963348/ /pubmed/29896416 http://dx.doi.org/10.14336/AD.2017.0517 Text en Copyright: © 2018 Zhang et al. http://creativecommons.org/licenses/by/2.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Orginal Article
Zhang, Meng
Deng, Yong-Ning
Zhang, Jing-Yi
Liu, Jie
Li, Yan-Bo
Su, Hua
Qu, Qiu-Min
SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway
title SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway
title_full SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway
title_fullStr SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway
title_full_unstemmed SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway
title_short SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway
title_sort sirt3 protects rotenone-induced injury in sh-sy5y cells by promoting autophagy through the lkb1-ampk-mtor pathway
topic Orginal Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963348/
https://www.ncbi.nlm.nih.gov/pubmed/29896416
http://dx.doi.org/10.14336/AD.2017.0517
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