Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of Phb1, likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria.

中文翻译：

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雪旺细胞中 Prohibitin1 缺失激活 mTORC1 和 c-Jun 可能将线粒体功能障碍与脱髓鞘联系起来


雪旺细胞 (SC) 线粒体迅速成为周围神经系统 (PNS) 髓磷脂维持的重要调节因子。然而，三七总皂苷线粒体功能障碍背景下脱髓鞘的机制尚不完全清楚。我们最近发现，SCs 中线粒体蛋白 Prohibitin 1 (PHB1) 的条件性消融会导致小鼠出现严重且快速进展的脱髓鞘性周围神经病变，但导致髓磷脂维持失败的机制仍不清楚。在这里，我们报告 mTORC1 和 c-Jun 在Phb1缺失的情况下持续激活，这可能是 SC 对线粒体损伤反应的一部分。此外，我们证明这些途径参与脱髓鞘过程，并且使用雷帕霉素抑制 mTORC1 可以部分挽救脱髓鞘病理。因此，我们认为 mTORC1 和 c-Jun 可能在 SC 线粒体扰动的背景下作为脱髓鞘的执行者发挥关键作用。