wlds reduces paraquat-induced cytotoxicity via sirt1 in non-neuronal cells by attenuating the depletion of nad该文就近年来关于百草枯所致细胞毒性发生世界减少通过sirt1在non-neuronal细胞衰减nad的损耗.pdfVIP

WldS Reduces Paraquat-Induced Cytotoxicity via SIRT1 in Non-Neuronal Cells by Attenuating the Depletion of NAD Qiujing Yu, Ting Wang, Xuexia Zhou, Jingxia Wu, Xingmiao Chen, Yang Liu, Dongmei Wu, Qiwei Zhai* Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Abstract WldS is a fusion protein with NAD synthesis activity, and has been reported to protect axonal and synaptic compartments of neurons from various mechanical, genetic and chemical insults. However, whether WldS can protect non-neuronal cells against toxic chemicals is largely unknown. Here we found that WldS significantly reduced the cytotoxicity of bipyridylium herbicides paraquat and diquat in mouse embryonic fibroblasts, but had no effect on the cytotoxicity induced by chromium (VI), hydrogen peroxide, etoposide, tunicamycin or brefeldin A. WldS also slowed down the death of mice induced by intraperitoneal injection of paraquat. Further studies demonstrated that WldS markedly attenuated mitochondrial injury including disruption of mitochondrial membrane potential, structural damage and decline of ATP induced by paraquat. Disruption of the NAD synthesis activity of WldS by an H112A or F116S point mutation resulted in loss of its protective function against paraquat-induced cell death. Furthermore, WldS delayed the decrease of intracellular NAD levels induced by paraquat. Similarly, treatment with NAD or its precursor nicotinamide mononucleotide attenuated paraquat-induced cytotoxicity and decline of ATP and NAD levels. In addition, we showed that SIRT1 was required for both exogenous NAD and WldS-mediated cellular protection