TY - JOUR
T1 - Melatonin antagonizes cadmium-induced neurotoxicity by activating the transcription factor EB-dependent autophagy–lysosome machinery in mouse neuroblastoma cells
AU - Li, Min
AU - Pi, Huifeng
AU - Yang, Zhiqi
AU - Reiter, Russel J.
AU - Xu, Shangcheng
AU - Chen, Xiaowei
AU - Chen, Chunhai
AU - Zhang, Lei
AU - Yang, Min
AU - Li, Yuming
AU - Guo, Pan
AU - Li, Gaoming
AU - Tu, Manyu
AU - Tian, Li
AU - Xie, Jia
AU - He, Mindi
AU - Lu, Yonghui
AU - Zhong, Min
AU - Zhang, Yanwen
AU - Yu, Zhengping
AU - Zhou, Zhou
N1 - Publisher Copyright:
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
PY - 2016/10/1
Y1 - 2016/10/1
N2 - Cadmium (Cd), a highly ubiquitous heavy metal, induces neurotoxicity. Melatonin, a major secretory product of the pineal gland, protects against Cd-induced neurotoxicity. However, the mechanism that accounts for this protection remains to be elucidated. Herein, we exposed mouse neuroblastoma cells (Neuro-2a cells) to different concentrations of cadmium chloride (CdCl2) (12.5, 25, and 50 μ mol L−1) for 24 hours. We showed that Cd inhibits autophagosome–lysosome fusion and impairs lysosomal function, subsequently leading to nerve cell death. In addition, Cd decreases the level of transcription factor EB (TFEB) but induces the nuclear translocation of TFEB, associated with compromised lysosomal function or a compensatory effect after the impairment of the autophagic flux. Moreover, compared to the 50-μ mol L−1 Cd group, administration of 1 μ mol L−1 melatonin increased “TFEB-responsive genes” (P<.05) and the levels of lysosomal-associated membrane protein (0.57±0.06 vs 1.00±0.11, P<.05), preserved lysosomal protease activity (0.52±0.01 vs 0.90±0.02, P<.05), maintained the lysosomal pH level (0.50±0.01 vs 0.87±0.05, P<.01), and enhanced autophagosome–lysosome fusion (0.05±0.00 vs 0.21±0.01, P<.01). Notably, melatonin enhanced TFEB expression (0.37±0.04 vs 0.72±0.07, P<.05) and nuclear translocation (2.81±0.08 vs 3.82±0.05, P<.05). Tfeb siRNA blocked the melatonin-mediated elevation in autophagy–lysosome machinery in Cd-induced neurotoxicity (P<.01). Taken together, these results uncover a potent role for TFEB-mediated autophagy in the pathogenesis of Cd-induced neurotoxicity, suggesting that control of the autophagic pathway by melatonin might provide an important clue for exploring potential targets for novel therapeutics of Cd-induced neurotoxicity.
AB - Cadmium (Cd), a highly ubiquitous heavy metal, induces neurotoxicity. Melatonin, a major secretory product of the pineal gland, protects against Cd-induced neurotoxicity. However, the mechanism that accounts for this protection remains to be elucidated. Herein, we exposed mouse neuroblastoma cells (Neuro-2a cells) to different concentrations of cadmium chloride (CdCl2) (12.5, 25, and 50 μ mol L−1) for 24 hours. We showed that Cd inhibits autophagosome–lysosome fusion and impairs lysosomal function, subsequently leading to nerve cell death. In addition, Cd decreases the level of transcription factor EB (TFEB) but induces the nuclear translocation of TFEB, associated with compromised lysosomal function or a compensatory effect after the impairment of the autophagic flux. Moreover, compared to the 50-μ mol L−1 Cd group, administration of 1 μ mol L−1 melatonin increased “TFEB-responsive genes” (P<.05) and the levels of lysosomal-associated membrane protein (0.57±0.06 vs 1.00±0.11, P<.05), preserved lysosomal protease activity (0.52±0.01 vs 0.90±0.02, P<.05), maintained the lysosomal pH level (0.50±0.01 vs 0.87±0.05, P<.01), and enhanced autophagosome–lysosome fusion (0.05±0.00 vs 0.21±0.01, P<.01). Notably, melatonin enhanced TFEB expression (0.37±0.04 vs 0.72±0.07, P<.05) and nuclear translocation (2.81±0.08 vs 3.82±0.05, P<.05). Tfeb siRNA blocked the melatonin-mediated elevation in autophagy–lysosome machinery in Cd-induced neurotoxicity (P<.01). Taken together, these results uncover a potent role for TFEB-mediated autophagy in the pathogenesis of Cd-induced neurotoxicity, suggesting that control of the autophagic pathway by melatonin might provide an important clue for exploring potential targets for novel therapeutics of Cd-induced neurotoxicity.
KW - autophagy
KW - cadmium
KW - lysosomal function
KW - melatonin
KW - neurotoxicity
KW - transcription factor EB
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U2 - 10.1111/jpi.12353
DO - 10.1111/jpi.12353
M3 - Article
C2 - 27396692
AN - SCOPUS:84986308291
SN - 0742-3098
SP - 353
EP - 369
JO - Journal of pineal research
JF - Journal of pineal research
ER -