Παρασκευή 14 Απριλίου 2017

Sirt3 confers protection against neuronal ischemia by inducing autophagy: Involvement of the AMPK-mTOR pathway

Publication date: July 2017
Source:Free Radical Biology and Medicine, Volume 108
Author(s): Shu-Hui Dai, Tao Chen, Xia Li, Kang-Yi Yue, Peng Luo, Li-Kun Yang, Jie Zhu, Yu-Hai Wang, Zhou Fei, Xiao-Fan Jiang
Sirtuin3 (Sirt3) is a member of the silent information regulator 2 (Sir2) family of proteins located in mitochondria that influences almost every major aspect of mitochondrial biology, including ATP generation and reactive oxygen species (ROS) production. Our previous study showed that Sirt3 exerts protective effects against oxidative stress in neuronal cells. In this study, we investigated the role of Sirt3 in neuronal ischemia using an oxygen and glucose deprivation (OGD) model. Sirt3 was up-regulated by OGD and overexpression of Sirt3 through lentivirus transfection significantly reduced OGD-induced lactate dehydrogenase (LDH) release and neuronal apoptosis. These effects were accompanied by reduced hydrogen dioxide (H2O2) production, enhanced ATP generation and preserved mitochondrial membrane potential (MMP). The results of immunocytochemistry and electron microscopy showed that Sirt3 increased autophagy in OGD-injured neurons, which was also confirmed by the increased expression of Beclin-1 as well as LC3-I to LC3-II conversion. In addition, the autophagy inhibitor 3-MA and bafilomycin A1 partially prevented the effects of Sirt3 on LDH release and apoptosis after OGD. The results of western blotting showed that overexpression of Sirt3 in cortical neurons markedly increased the phosphorylation of AMPK, whereas the phosphor-mTOR (p-mTOR) levels decreased both in the presence and absence of OGD insult. Furthermore, pre-treatment with the AMPK inhibitor compound C partially reversed the protective effects of Sirt3. Taken together, these findings demonstrate that Sirt3 protects against OGD insult by inducing autophagy through regulation of the AMPK-mTOR pathway and that Sirt3 may have therapeutic value for protecting neurons from cerebral ischemia.

Graphical abstract

image


from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2nLFWpK
via IFTTT

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου

Δημοφιλείς αναρτήσεις