Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process
Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process
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DOI：
10.1038/cdd.2014.35
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发表时间：
2014-08-01
影响因子：
12.4
通讯作者：
Pinton, P.
中科院分区：
文献类型：
--
作者：
Bonora, M.;De Marchi, E.;Pinton, P.
线粒体缺陷，影响参数，如线粒体数量和形状，呼吸链复合物组分和氧化应激标志物的水平，已与多发性硬化症的出现和进展。然而，线粒体生理学从未监测少突胶质细胞祖细胞（OPC）的分化过程中，特别是在前炎症细胞因子的挑战OPC。在这里，我们表明，肿瘤坏死因子α（TNF-α）抑制OPC分化，伴随着改变线粒体钙摄取，线粒体膜电位，呼吸复合物I的活性，以及增加活性氧的生产。用线粒体解偶联剂（FCCP）处理以模拟线粒体损伤也导致细胞在祖细胞阶段积累。有趣的是，AMP活化蛋白激酶（AMPK）水平在TNF-α暴露期间增加并抑制OPC分化。总体而言，我们的数据表明，TNF-α诱导代谢变化，由线粒体损伤和AMPK激活驱动，导致OPC分化的抑制。
Mitochondrial defects, affecting parameters such as mitochondrial number and shape, levels of respiratory chain complex components and markers of oxidative stress, have been associated with the appearance and progression of multiple sclerosis. Nevertheless, mitochondrial physiology has never been monitored during oligodendrocyte progenitor cell (OPC) differentiation, especially in OPCs challenged with proinflammatory cytokines. Here, we show that tumor necrosis factor alpha (TNF-alpha) inhibits OPC differentiation, accompanied by altered mitochondrial calcium uptake, mitochondrial membrane potential, and respiratory complex I activity as well as increased reactive oxygen species production. Treatment with a mitochondrial uncoupler (FCCP) to mimic mitochondrial impairment also causes cells to accumulate at the progenitor stage. Interestingly, AMP-activated protein kinase (AMPK) levels increase during TNF-a exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-alpha induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation.