Bonora M, De Marchi E, Patergnani S, Suski J M, Celsi F, Bononi A, Giorgi C, Marchi S, Rimessi A, Duszyński J, Pozzan T, Wieckowski M R, Pinton P
Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
1] Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy [2] Department of Biochemistry, Nencki Institute of Experimental Biology, Warsaw, Poland.
Cell Death Differ. 2014 Aug;21(8):1198-208. doi: 10.1038/cdd.2014.35. Epub 2014 Mar 21.
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-α) 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-α exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-α induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation.
线粒体缺陷，影响线粒体数量和形态、呼吸链复合体成分水平以及氧化应激标志物等参数，已与多发性硬化症的出现和进展相关。然而，在少突胶质前体细胞（OPC）分化过程中，尤其是在用促炎细胞因子刺激的OPC中，线粒体生理学从未被监测过。在这里，我们表明肿瘤坏死因子α（TNF-α）抑制OPC分化，同时伴有线粒体钙摄取、线粒体膜电位和呼吸复合体I活性改变以及活性氧生成增加。用线粒体解偶联剂（FCCP）处理以模拟线粒体损伤也会导致细胞在祖细胞阶段积累。有趣的是，在TNF-α暴露期间，AMP激活的蛋白激酶（AMPK）水平升高并抑制OPC分化。总体而言，我们的数据表明TNF-α诱导由线粒体损伤和AMPK激活驱动的代谢变化，导致OPC分化受到抑制。
