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  2. Manganese induces autophagy dysregulation: The role of S-nitrosylation in regulating autophagy related proteins in vivo and in vitro

Manganese induces autophagy dysregulation: The role of S-nitrosylation in regulating autophagy related proteins in vivo and in vitro

  • Sci Total Environ. 2020 Jan 1;698:134294. doi: 10.1016/j.scitotenv.2019.134294.
Zhuo Ma 1 Can Wang 1 Chang Liu 1 Dong-Ying Yan 1 Xuan Tan 1 Kuan Liu 1 Meng-Jiao Jing 1 Yu Deng 1 Wei Liu 1 Bin Xu 2
Affiliations

Affiliations

  • 1 Department of Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, People's Republic of China.
  • 2 Department of Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, People's Republic of China. Electronic address: bxu10@cmu.edu.cn.
Abstract

Exposure to excess levels of manganese (Mn) may lead to nitrosative stress and neurotoxic effects on the central nervous system (CNS). The dysfunction of Autophagy correlates with Mn-induced nitrosative stress; however, the exact mechanism of Mn-mediated Autophagy dysfunction is still unclear. Three S-nitrosylated target proteins, namely, JNK, Bcl-2, and IKKβ, were classified as the pivotal signaling pathway mediators that could play a role in the regulation of Autophagy. To reveal whether these three proteins were involved in Mn-mediated Autophagy dysregulation, we studied the effects of Mn on C57/BL6 mice and human neuroblastoma cells. Exposing the mice or cells, to 300 μmol/kg or 200 μM Mn, inhibited the degradation system of the autophagy-lysosome pathway. Additionally, in Mn-treated mice or cells, S-nitrosylated JNK, Bcl-2, and IKKβ increased while the level of their phosphorylation reduced. The interaction of Beclin1 and Bcl-2 significantly increased in response to 200 μM Mn, whereas the decrease in phosphorylation of AMPK activated the mTOR pathway. We then used 20 μM 1400 W, an iNOS-specific inhibitor, to neutralize the nitrosative stress induced by Mn. Our results show that 1400 W reduced the S-nitrosylated JNK, Bcl-2, and Ikkβ and relieved their downstream signaling molecular functions. Moreover, pretreatment with 20 μM 1400 W alleviated Mn-induced autophagic dysregulation and nerve cell injury. These findings revealed that S-nitrosylated JNK, Bcl-2, and IKKβ are crucial signaling molecules in the Mn-mediated autophagic dysfunction.

Keywords

Autophagy dysregulation; Mn; Neurotoxicity; Nitrosative stress.

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