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Aging and disease    2018, Vol. 9 Issue (2) : 273-286     DOI: 10.14336/AD.2017.0517
Orginal Article |
SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway
Zhang Meng1, Deng Yong-Ning1, Zhang Jing-Yi1, Liu Jie1, Li Yan-Bo1, Su Hua2, Qu Qiu-Min1,*
1Department of Neurology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China.
2Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, USA.
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Abstract  

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.

Keywords Parkinson’s disease      SIRT3      Autophagy      α-synuclein      Oxidative stress      mitochondrial dysfunction     
Corresponding Authors: Qu Qiu-Min   
About author:

These authors contributed equally.

Issue Date: 01 April 2018
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Zhang Meng
Deng Yong-Ning
Zhang Jing-Yi
Liu Jie
Li Yan-Bo
Su Hua
Qu Qiu-Min
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Zhang Meng,Deng Yong-Ning,Zhang Jing-Yi, et al. SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway[J]. Aging and disease, 2018, 9(2): 273-286.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.0517     OR     http://www.aginganddisease.org/EN/Y2018/V9/I2/273
Figure 1.  Differentiation of SH-SY5Y cells. (A) Undifferentiated SH-SY5Y cells cultured in 10% complete medium for 5 days. (B) Differentiated SH-SY5Y cells cultured in 1% cultural medium with RA (10 μM) for 5 days.
Figure 2.  SIRT3 increases autophagy in human neuroblastoma SH-SY5Y cells. Lysates from cells untreated, or treated with SIRT3-NC or SIRT3i-NC (non-targeting lentivirus), LV-SIRT3 (Lentivirus with a SIRT3 overexpression gene) or LV-SIRT3i (Lentivirus with a SIRT3 silencing gene) were prepared and analyzed by western blotting. (A) SIRT3 overexpression and silencing using lentiviruses were identified by SIRT3 immunoblotting with an antibody against SIRT3. Autophagy induction by SIRT3 was determined by the LC3II and Beclin1 protein levels with an antibody against LC3B and Beclin 1. β-actin is used as a loading control. Mean ± SEM, n=3. Bar graphs show the quantification of the relative levels of SIRT3 (B), LC3II (C) and Beclin 1 (F). (D) SH-SY5Y cells with or without SIRT3 overexpression were treated with 100 nM Bafilomycin A1 for 100 min. Cell lysates were prepared and analyzed by western blotting. (E) Bar graphs show the quantification of LC3II level ratios between WT+BA and WT, Vehicle+BA and Vehicle, SIRT3+BA and SIRT3 groups. β-actin is used as a loading control. Mean ± SEM, n=3. (G) Ultrastructural SH-SY5Y cells in WT, Vehicle (NT-lentivirus) and LV-SIRT3 (SIRT3+) groups. Black arrows indicate mitochondria. White arrows show different stages of autophagic vascuoles: * represents an early autophagic vacuole (AVi); ** represents a degradative autophagic vacuole (AVd). An AVi can be identified by its contents (morphologically intact cytoplasm). The AVd contains partially degraded contents. Scale bars, 500 nm.
Figure 3.  SIRT3 prevents rotenone-induced cell death in human neuroblastoma SH-SY5Y cells by upregulating autophagy. The SH-SY5Y cells with or without SIRT3 overexpression cultured in non-serum growth medium were treated with 60 μM rotenone for 24 h. Five millimolar 3-MA was added 1 h before rotenone. (A) Then, the treated cells were subjected to the MTT assay. Bar graph shows the quantification of cell viability determined by MTT assay in WT, WT+Rot, WT+3-MA, Vehicle, Vehicle+Rot, Vehicle+3-MA, SIRT3+, SIRT3+Rot, and SIRT3+Rot+3-MA groups. Mean ± SEM, n=3. #: P<0.001 vs. Vehicle+Rotenone. After treatment as described above, cells were harvested, stained with 7-AAD (Y-axis) and PE-Annexin V (X-axis). Scatter diagram (B) and bar graph (C) show the flow cytometric analysis of staining from WT, WT+Rot, WT+3-MA, Vehicle, Vehicle+Rot, Vehicle+3-MA, SIRT3+, SIRT3+Rot, and SIRT3+Rot+3-MA groups. The apoptotic rate= [AnnexinV-PE(+)7-AAD(-)cells + AnnexinV-PE(+)7-AAD(+)cells]/total cells×100%. Mean ± SEM, n=3. Rot=Rotenone. δ: P<0.001 vs. Vehicle+Rotenone.
Figure 4.  SIRT3 enhances the clearance of α-synuclein by upregulating autophagy. (A) SH-SY5Y cells with or without SIRT3 overexpression cultured in non-serum growth medium were treated with 60μM rotenone for 24h. Five millimolar 3-MA was added 1h before rotenone. The cells were immunostained for α-synuclein (red). DAPI staining was used to mark the position of the nuclei. Scale bars=50 μm. (B) A bar graph shows the quantification of mean fluorescence intensity of α-synuclein in each group. Mean ± SEM, n=3. δ: P<0.001 vs. Vehicle+Rotenone. (C) The cells were treated in the same way as mentioned in A, and cell lysates were prepared and analyzed by western blotting using antibodies against α-synuclein. LC3 and Beclin 1 immunoblotting were performed to test the autophagic level under rotenone or 3-MA treatment. (D, E, F) Bar graphs show the quantification of the relative level of α-synuclein, LC3II and Beclin1 in each group. β-actin is used as a loading control. Mean ± SEM, n=3. #: P<0.001 vs. Vehicle+Rotenone. &: P<0.01 vs. WT. σ: P<0.001 vs. Vehicle. $: P<0.001 vs. SIRT3.
Figure 5.  SIRT3 upregulates intracellular SOD and GSH levels, prevents rotenone-induced ROS generation and MMP collapse in SH-SY5Y cells by upregulating autophagy. The SH-SY5Y cells with or without SIRT3 overexpression cultured in serum-free growth medium were treated with 60μM rotenone for 24 h. Five millimolar 3-MA was added 1h before rotenone. The cells were harvested and stained with DCFH-DA. (A) ROS levels were measured by a fluorescence-activated cell sorter. (B) Bar graph shows the quantification of ROS levels. Mean ± SEM, n=3. δ: P<0.001 vs. Vehicle+Rotenone. The cells were collected for quantification of intracellular SOD (C), GSH (D) using the corresponding detecting kits. Mean ± SEM, n=3. #: P<0.05 vs. Vehicle+Rotenone. δ: P<0.001 vs. Vehicle+Rotenone. (E) MMP was measured by JC-1 aggregates/monomer using a flow cytometer. (F) The bar graph shows the quantification of JC-1 aggregates/monomer levels in each group. Mean ± SEM, n=3. σ: P<0.001 vs. Vehicle+Rotenone.
Figure 6.  SIRT3 induces autophagy through the LKB1-AMPK-mTOR pathway. (A) The SH-SY5Y cells with or without SIRT3 overexpression were treated with 40 μM Dorsomorphin or control for 100 min. The cell lysates were analyzed by western blotting with the indicated antibodies. Data show the quantification of the p-LKB1/LKB1 ratio (B), p-AMPK/AMPK ratio (C), p-mTOR/mTOR levels (D) and LC3II (E). β-actin is used as a loading control. #: P<0.001 vs. WT, $: P<0.001 vs. Vehicle, &: P<0.001 vs. SIRT3+. Mean ± SEM, n=3.
Figure 7.  A schematic model for SIRT3-induced autophagy and its underlying mechanism in SH-SY5Y cells following rotenone treatment. SIRT3 overexpression leads to an acceleration of LKB1 activation (phosphorylation) and downstream AMPK activation, thus decreasing mTOR phosphorylation and initiating an autophagic response. In a rotenone-induced Parkinson cell model, there is enhanced α-synuclein aggregation, accelerated oxidative stress and increased mitochondria dysfunction. With SIRT3 overexpression and induced autophagic levels, these injuries are ameliorated. Blocking autophagy using 3-MA abolished the protective effect. Our results suggest that SIRT3 protects cells from rotenone by generating autophagy. The LKB1-AMPK-mTOR pathway is involved in the generation.
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