Mitochondrial dysfunction may activate innate immunity, e.g. upon abnormal handling of mitochondrial DNA in TFAM mutants or in altered mitophagy. Recent reports showed that also deletion of mitochondrial matrix peptidase ClpP in mice triggers transcriptional upregulation of inflammatory factors. Here, we studied ClpP-null mouse brain at two ages and mouse embryonal fibroblasts, to identify which signaling pathways are responsible, employing mass spectrometry, subcellular fractionation, immunoblots, and reverse transcriptase polymerase chain reaction. Several mitochondrial unfolded protein response factors showed accumulation and altered migration in blue-native gels, prominently the co-chaperone DNAJA3. Its mitochondrial dysregulation increased also its extra-mitochondrial abundance in the nucleus, a relevant observation given that DNAJA3 modulates innate immunity. Similar observations were made for STAT1, a putative DNAJA3 interactor. Elevated expression was observed not only for the transcription factors Stat1/2, but also for two interferon-stimulated genes (Ifi44, Gbp3). Inflammatory responses were strongest for the RLR pattern recognition receptors (Ddx58, Ifih1, Oasl2, Trim25) and several cytosolic nucleic acid sensors (Ifit1, Ifit3, Oas1b, Ifi204, Mnda). The consistent dysregulation of these factors from an early age might influence also human Perrault syndrome, where ClpP loss-of-function leads to early infertility and deafness, with subsequent widespread neurodegeneration.

线粒体功能障碍可能会激活先天免疫，例如在 TFAM 突变体中线粒体 DNA 的异常处理或改变的线粒体自噬中。最近的报道表明，小鼠线粒体基质肽酶 ClpP 的缺失也会触发炎症因子的转录上调。在这里，我们研究了两个年龄的 ClpP-null 小鼠大脑和小鼠胚胎成纤维细胞，以确定哪些信号通路负责，采用质谱、亚细胞分离、免疫印迹和逆转录酶聚合酶链反应。几种线粒体未折叠蛋白反应因子在蓝色天然凝胶中显示出积累和改变的迁移，特别是辅助伴侣 DNAJA3。它的线粒体失调也增加了其在细胞核中的线粒体外丰度，鉴于 DNAJA3 调节先天免疫，这是一个相关的观察结果。对假定的 DNAJA3 相互作用子 STAT1 进行了类似的观察。不仅转录因子观察到表达升高Stat1/2，但也适用于两个干扰素刺激的基因（Ifi44，Gbp3）。RLR 模式识别受体（Ddx58、Ifih1、Oasl2、Trim25）和几种胞质核酸传感器（Ifit1、Ifit3、Oas1b、Ifi204、Mnda）的炎症反应最强。从小这些因素的持续失调也可能影响人类 Perrault 综合征，其中 ClpP 功能丧失导致早期不育和耳聋，随后出现广泛的神经退行性变。