Dermatomyositis (DM) is an autoimmune disease associated with enhanced type I interferon (IFN) signalling in skeletal muscle, but the mechanisms underlying muscle dysfunction and inflammation perpetuation remain unknown. Transcriptomic analysis of early untreated DM muscles revealed that the main cluster of down-regulated genes was mitochondria-related. Histochemical, electron microscopy, and in situ oxygraphy analysis showed mitochondrial abnormalities, including increased reactive oxygen species (ROS) production and decreased respiration, which was correlated with low exercise capacities and a type I IFN signature. Moreover, IFN-β induced ROS production in human myotubes was found to contribute to mitochondrial malfunctions. Importantly, the ROS scavenger N-acetyl cysteine (NAC) prevented mitochondrial dysfunctions, type I IFN-stimulated transcript levels, inflammatory cell infiltrate, and muscle weakness in an experimental autoimmune myositis mouse model. Thus, these data highlight a central role of mitochondria and ROS in DM. Mitochondrial dysfunctions, mediated by IFN-β induced-ROS, contribute to poor exercise capacity. In addition, mitochondrial dysfunctions increase ROS production that drive type I IFN-inducible gene expression and muscle inflammation, and may thus self-sustain the disease. Given that current DM treatments only induce partial recovery and expose to serious adverse events (including muscular toxicity), protecting mitochondria from dysfunctions may open new therapeutic avenues for DM.

皮肌炎（DM）是与骨骼肌中增强的I型干扰素（IFN）信号传导相关的自身免疫性疾病，但肌肉功能障碍和炎症永存的机制尚不清楚。早期未经处理的DM肌肉的转录组学分析显示，下调基因的主要簇与线粒体相关。组织化学，电子显微镜和原位氧像分析显示线粒体异常，包括增加的活性氧（ROS）产生和呼吸减少，这与运动能力低和I型IFN签名有关。此外，发现IFN-β诱导的人肌管中的ROS产生导致线粒体功能障碍。重要的是，ROS清除剂N-乙酰半胱氨酸（NAC）在实验性自身免疫性肌炎小鼠模型中预防了线粒体功能障碍，I型IFN刺激的转录水平，炎性细胞浸润和肌肉无力。因此，这些数据突出了线粒体和ROS在DM中的核心作用。由IFN-β诱导的ROS介导的线粒体功能障碍导致运动能力差。此外，线粒体功能障碍会增加ROS的产生，从而驱动I型IFN诱导型基因表达和肌肉发炎，从而使疾病自我维持。鉴于当前的DM治疗仅能诱导部分恢复并暴露于严重的不良事件（包括肌肉毒性），因此保护线粒体免受功能障碍的影响可能为DM开辟新的治疗途径。