Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+).
Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+).
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DOI：
10.1038/cddis.2014.166
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发表时间：
2014-05-08
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
通过组学技术和生物信息学数据处理对毒性途径网络的评估为二十一世纪的新毒理学铺平了道路。特别是，在达到不归点之前，毒物处理细胞中发生的上游反应网络仍然很少被探索。我们通过代谢组学（质谱）和转录组学（微阵列和深度测序）相结合的方法研究了模型神经毒物1-甲基-4-苯基吡啶（MPP+）的影响，以提供关于最早细胞适应压力的无偏数据。将神经前体细胞（LUHMES）分化为完全有丝分裂后人多巴胺能神经元的同质培养物，然后暴露于线粒体呼吸链抑制剂MPP+（5 μM）。处理后18-24 h，细胞内ATP和线粒体完整性仍接近对照水平，但观察到明显的转录组和代谢组变化。关于改变的葡萄糖流量、磷酸肌酸消耗和氧化应激的数据（例如，甲硫氨酸亚砜的形成）证实了该方法的有效性。新的发现与核旁斑耗竭以及转硫途径分支的早期激活有关，以增加谷胱甘肽。我们的数据的生物信息学分析确定转录因子ATF-4作为早期反应的上游调节因子。这一信号通路和谷胱甘肽生产的适应性增加的研究结果证实了生物化学。代谢和转录谱分析提供了关于多个原发性和继发性变化的补充信息，这些变化有助于对MPP+的细胞反应。因此，组合的“组学”分析是一种新的无偏见的方法来解开最早的代谢变化，其平衡决定最终的细胞命运。
Assessment of the network of toxicity pathways by Omics technologies and bioinformatic data processing paves the road toward a new toxicology for the twenty-first century. Especially, the upstream network of responses, taking place in toxicant-treated cells before a point of no return is reached, is still little explored. We studied the effects of the model neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) by a combined metabolomics (mass spectrometry) and transcriptomics (microarrays and deep sequencing) approach to provide unbiased data on earliest cellular adaptations to stress. Neural precursor cells (LUHMES) were differentiated to homogeneous cultures of fully postmitotic human dopaminergic neurons, and then exposed to the mitochondrial respiratory chain inhibitor MPP+ (5 μM). At 18–24 h after treatment, intracellular ATP and mitochondrial integrity were still close to control levels, but pronounced transcriptome and metabolome changes were seen. Data on altered glucose flux, depletion of phosphocreatine and oxidative stress (e.g., methionine sulfoxide formation) confirmed the validity of the approach. New findings were related to nuclear paraspeckle depletion, as well as an early activation of branches of the transsulfuration pathway to increase glutathione. Bioinformatic analysis of our data identified the transcription factor ATF-4 as an upstream regulator of early responses. Findings on this signaling pathway and on adaptive increases of glutathione production were confirmed biochemically. Metabolic and transcriptional profiling contributed complementary information on multiple primary and secondary changes that contribute to the cellular response to MPP+. Thus, combined ‘Omics' analysis is a new unbiased approach to unravel earliest metabolic changes, whose balance decides on the final cell fate.
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影响因子：
3.8
作者：
Drechsel, Derek A.;Liang, Li-Ping;Patel, Manisha
通讯作者：
Patel, Manisha
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1080/10937404.2010.483176
发表时间：
2010-02
期刊：
Journal of toxicology and environmental health. Part B, Critical reviews
影响因子：
--
作者：
Krewski D;Acosta D Jr;Andersen M;Anderson H;Bailar JC 3rd;Boekelheide K;Brent R;Charnley G;Cheung VG;Green S Jr;Kelsey KT;Kerkvliet NI;Li AA;McCray L;Meyer O;Patterson RD;Pennie W;Scala RA;Solomon GM;Stephens M;Yager J;Zeise L
通讯作者：
Zeise L
影响因子：
5.8
作者：
Karreman, C
通讯作者：
Karreman, C
影响因子：
2.5
作者：
DESOLE, MS;ESPOSITO, G;MIELE, E
通讯作者：
MIELE, E