Journal
SCIENCE OF THE TOTAL ENVIRONMENT
Volume 698, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.scitotenv.2019.134294
Keywords
Mn; Nirrosative stress; Neurotoxicity; Autophagy dysregulation
Categories
Funding
- National Natural Science Foundation of China [81773377]
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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 IKK beta, 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 mu mol/kg or 200 mu M Mn, inhibited the degradation system of the autophagy-lysosome pathway. Additionally, in Mn-treated mice or cells, S-nitrosylated JNK, Bcl-2, and IKK beta increased while the level of their phosphorylation reduced. The interaction of Beclinl and Bcl-2 significantly inaeased in response to 200 mu M Mn, whereas the decrease in phosphorylation of AMPK activated the mTOR pathway. We then used 20 mu M 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 IKK beta and relieved their downstream signaling molecular functions. Moreover, pretreatment with 20 mu M 1400 W alleviated Mn-induced autophagic dysregulation and nerve cell injury. These findings revealed that S-nitrosylated JNK, Bcl-2, and IKK beta are crucial signaling molecules in the Mn-mediated autophagic dysfunction. (C) 2019 Elsevier B.V. All rights reserved.
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