Manganese exposure induces neuroinflammation by impairing mitochondrial dynamics in astrocytes.
Manganese exposure induces neuroinflammation by impairing mitochondrial dynamics in astrocytes.
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DOI：
10.1016/j.neuro.2017.05.009
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发表时间：
2018-01
期刊：
影响因子：
3.4
通讯作者：
Kanthasamy A
中科院分区：
文献类型：
--
作者：
Sarkar S;Malovic E;Harischandra DS;Ngwa HA;Ghosh A;Hogan C;Rokad D;Zenitsky G;Jin H;Anantharam V;Kanthasamy AG;Kanthasamy A
慢性锰（Mn）暴露可诱导神经毒性，其特征为基底神经节锥体外系运动系统受损导致的帕金森症状。线粒体功能障碍和氧化应激被认为是锰神经毒性的关键病理生理特征。最近的证据表明星形胶质细胞作为锰神经毒性的主要目标，因为锰主要在星形胶质细胞中积累。然而，锰诱导的星形胶质细胞功能障碍及其在金属神经毒性中的作用的主要机制尚未完全了解。在这项研究中，我们研究了锰神经毒性中线粒体功能障碍和星形胶质细胞炎症之间的相互关系。我们首先评估锰暴露是否改变培养的星形胶质细胞中的线粒体生物能量学。通过MTS试验评估的代谢活性显示，24 h时在原代小鼠星形胶质细胞（PMA）中Mn的IC50为92.68 μ M，在人星形胶质细胞U373细胞系中为50.46 μ M。Mn处理降低了线粒体质量，表明线粒体功能和生物发生受损，这通过线粒体融合蛋白-2（一种充当线粒体自噬的泛素化靶标的蛋白质）的mRNA的显著降低来证实。此外，锰增加线粒体圆形，表明线粒体分裂增强。海马锰处理的星形胶质细胞的生物能量学状态的分析表明，锰显着损害的基础线粒体耗氧率以及ATP相关的呼吸速率。Mn对线粒体能量缺乏的影响进一步得到ATP产生减少的支持。锰暴露的初级星形胶质细胞也表现出严重的静止能量表型，这是由寡霉素不能增加细胞外酸化率证实。由于星形胶质细胞调节CNS中的免疫功能，我们还评估了Mn是否调节星形胶质细胞炎症。锰暴露不仅刺激星形胶质细胞释放促炎性细胞因子，而且加重聚集的α-synuclein诱导的炎症反应。新的靶向抗氧化剂mito-apocynin显著减弱了Mn诱导的炎症基因表达，进一步支持线粒体功能障碍和氧化应激在介导星形胶质细胞增生中的作用。最后，鼻内递送Mn在体内升高GFAP和降低嗅球中的TH水平，清楚地支持星形胶质细胞参与Mn诱导的多巴胺能神经毒性。总的来说，我们的研究表明，锰驱动星形胶质细胞中的促炎事件通过损害线粒体生物能量学。
Chronic manganese (Mn) exposure induces neurotoxicity, which is characterized by Parkinsonian symptoms resulting from impairment in the extrapyramidal motor system of the basal ganglia. Mitochondrial dysfunction and oxidative stress are considered key pathophysiological features of Mn neurotoxicity. Recent evidence suggests astrocytes as a major target of Mn neurotoxicity since Mn accumulates predominantly in astrocytes. However, the primary mechanisms underlying Mn-induced astroglial dysfunction and its role in metal neurotoxicity are not completely understood. In this study, we examined the interrelationship between mitochondrial dysfunction and astrocytic inflammation in Mn neurotoxicity. We first evaluated whether Mn exposure alters mitochondrial bioenergetics in cultured astrocytes. Metabolic activity assessed by MTS assay revealed an IC50 of 92.68 μM Mn at 24 h in primary mouse astrocytes (PMAs) and 50.46 μM in the human astrocytic U373 cell line. Mn treatment reduced mitochondrial mass, indicative of impaired mitochondrial function and biogenesis, which was substantiated by the significant reduction in mRNA of mitofusin-2, a protein that serves as a ubiquitination target for mitophagy. Furthermore, Mn increased mitochondrial circularity indicating augmented mitochondrial fission. Seahorse analysis of bioenergetics status in Mn-treated astrocytes revealed that Mn significantly impaired the basal mitochondrial oxygen consumption rate as well as the ATP-linked respiration rate. The effect of Mn on mitochondrial energy deficits was further supported by a reduction in ATP production. Mn-exposed primary astrocytes also exhibited a severely quiescent energy phenotype, which was substantiated by the inability of oligomycin to increase the extracellular acidification rate. Since astrocytes regulate immune functions in the CNS, we also evaluated whether Mn modulates astrocytic inflammation. Mn exposure in astrocytes not only stimulated the release of proinflammatory cytokines, but also exacerbated the inflammatory response induced by aggregated α-synuclein. The novel mitochondria-targeted antioxidant, mito-apocynin, significantly attenuated Mn-induced inflammatory gene expression, further supporting the role of mitochondria dysfunction and oxidative stress in mediating astrogliosis. Lastly, intranasal delivery of Mn in vivo elevated GFAP and depressed TH levels in the olfactory bulbs, clearly supporting the involvement of astrocytes in Mn-induced dopaminergic neurotoxicity. Collectively, our study demonstrates that Mn drives proinflammatory events in astrocytes by impairing mitochondrial bioenergetics.
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3.4
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