Wld(S) reduces paraquat-induced cytotoxicity via SIRT1 in non-neuronal cells by attenuating the depletion of NAD.
Wld(S) reduces paraquat-induced cytotoxicity via SIRT1 in non-neuronal cells by attenuating the depletion of NAD.
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DOI：
10.1371/journal.pone.0021770
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zhai Q
中科院分区：
文献类型：
--
作者：
Yu Q;Wang T;Zhou X;Wu J;Chen X;Liu Y;Wu D;Zhai Q
wld是一种具有NAD合成活性的融合蛋白，据报道，它可以保护神经元的轴突和突触区室免受各种机械、遗传和化学损伤。然而，wds是否能够保护非神经元细胞免受有毒化学物质的侵害在很大程度上是未知的。本研究发现，wds显著降低了联吡啶类除草剂百草枯和双喹菊酯对小鼠胚胎成纤维细胞的细胞毒性，但对铬（VI）、过氧化氢、etoposide、tunicamycin和brefeldin a诱导的细胞毒性没有影响。wds还减缓了腹腔注射百草枯诱导的小鼠死亡。进一步的研究表明，wds显著减轻了百草枯引起的线粒体损伤，包括线粒体膜电位的破坏、结构损伤和ATP的下降。通过H112A或F116S点突变破坏wld的NAD合成活性，导致其对百草枯诱导的细胞死亡的保护功能丧失。此外，wds延缓了百草枯诱导的细胞内NAD水平的下降。同样，用NAD或其前体烟酰胺单核苷酸处理可减轻百草枯诱导的细胞毒性和ATP和NAD水平的下降。此外，我们发现SIRT1是外源性NAD和wld介导的抗百草枯细胞保护所必需的。这些发现提示NAD和SIRT1介导了wld对百草枯诱导的细胞毒性的保护作用，为wld对神经元和非神经元细胞的保护作用机制提供了新的线索，并提示NAD消耗的衰减可能有效减轻百草枯中毒。
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 against paraquat. These findings suggest that NAD and SIRT1 mediate the protective function of WldS against the cytotoxicity induced by paraquat, which provides new clues for the mechanisms underlying the protective function of WldS in both neuronal and non-neuronal cells, and implies that attenuation of NAD depletion may be effective to alleviate paraquat poisoning.
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影响因子：
25
作者：
Mack, TGA;Reiner, M;Coleman, MP
通讯作者：
Coleman, MP
影响因子：
3.4
作者：
LUNN, ER;PERRY, VH;GORDON, S
通讯作者：
GORDON, S
影响因子：
5.7
作者：
Chen, Li-Hua;Fang, Jing;Lin, Xu
通讯作者：
Lin, Xu
影响因子：
11.8
作者：
Fulco, Marcella;Cen, Yana;Sartorelli, Vittorio
通讯作者：
Sartorelli, Vittorio
DOI：
10.1523/jneurosci.4065-10.2011
发表时间：
2011-01-19
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Barrientos SA;Martinez NW;Yoo S;Jara JS;Zamorano S;Hetz C;Twiss JL;Alvarez J;Court FA
通讯作者：
Court FA