Date Published: April 1, 2018
Publisher: JKL International LLC
Author(s): Meng Zhang, Yong-Ning Deng, Jing-Yi Zhang, Jie Liu, Yan-Bo Li, Hua Su, Qiu-Min Qu.
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.
In this study, we report that SIRT3 protects rotenone-induced SH-SY5Y cell damage by upregulating autophagy, where it increases cell viability and decreases cell apoptosis, attenuates the accumulation of α-synuclein, increases intracellular SOD and GSH levels, ameliorates rotenone-induced ROS generation, and preserves MMP reduction in SH-SY5Y cells. These effects could be blocked upon the inhibition of autophagy. We also demonstrated that the modulation of autophagy by SIRT3 is through the activation of the LKB1-AMPK-mTOR signaling pathway (Fig. 7).