The Mitochondria-Regulated Immune Pathway Activated in the C. elegans Intestine Is Neuroprotective.
The Mitochondria-Regulated Immune Pathway Activated in the C. elegans Intestine Is Neuroprotective.
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DOI：
10.1016/j.celrep.2016.07.077
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发表时间：
2016-08-30
期刊：
影响因子：
8.8
通讯作者：
Prahlad V
中科院分区：
文献类型：
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作者：
Chikka MR;Anbalagan C;Dvorak K;Dombeck K;Prahlad V
起源于神经系统外的免疫介质可以影响神经元的健康。然而，它们在神经变性中的作用在很大程度上仍然未知。在这里，我们表明，p38 MAPK介导的免疫途径激活的肠细胞的秀丽隐杆线虫线粒体功能障碍后，保护神经元的细胞非自主的方式。具体地说，鱼藤酮诱导的线粒体复合物I功能障碍激活了C.优雅的肠道中p38 MAPK的激活具有神经保护作用。增强肠细胞中p38 MAPK介导的免疫途径单独抑制鱼藤酮诱导的多巴胺能神经元损失，而在肠中下调它加剧神经变性。p38 MAPK/ATF-7免疫途径调节自噬，并需要自噬和PTEN诱导的推定激酶PINK-1来赋予神经保护作用。因此，线粒体损伤通过免疫途径诱导线粒体的清除，保护生物体免受线粒体功能障碍的毒性作用。我们认为，线粒体受到先天免疫机制的持续监视。Chikka等发现，线粒体复合物I损伤激活了肠内p38 MAPK/ATF-7信号通路。优美的肠中p38 MAPK/ATF-7免疫途径的激活具有神经保护作用，足以防止鱼藤酮诱导的多巴胺能神经元变性。
Immunological mediators that originate outside the nervous system can affect neuronal health. However, their roles in neurodegeneration remain largely unknown. Here, we show that the p38MAPK-mediated immune pathway activated in intestinal cells of Caenorhabditis elegans upon mitochondrial dysfunction protects neurons in a cell-non-autonomous fashion. Specifically, mitochondrial complex I dysfunction induced by rotenone activates the p38MAPK/CREB/ATF-7-dependent innate immune response pathway in intestinal cells of C. elegans. Activation of p38MAPK in the gut is neuroprotective. Enhancing the p38MAPK-mediated immune pathway in intestinal cells alone suppresses rotenone-induced dopaminergic neuron loss, while downregulating it in the intestine exacerbates neurodegeneration. The p38MAPK/ATF-7 immune pathway modulates autophagy and requires autophagy and the PTEN-induced putative kinase PINK-1 for conferring neuroprotection. Thus, mitochondrial damage induces the clearance of mitochondria by the immune pathway, protecting the organism from the toxic effects of mitochondrial dysfunction. We propose that mitochondria are subject to constant surveillance by innate immune mechanisms. Chikka et al. find that mitochondrial complex I damage activates the p38MAPK/ATF-7 signaling pathway in the intestine of C. elegans. Activation of the p38MAPK/ATF-7 immune pathway in the intestine is neuroprotective and sufficient to prevent rotenone-induced degeneration of dopaminergic neurons.
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