细菌产物CNF1通过其对RhoGTPases的作用,正在成为以线粒体功能障碍为特征的选定神经系统疾病中涉及的关键信号通路的调节剂。线粒体损伤被认为在Rett综合征(RTT)的重要机制中起着关键作用。一种严重的神经系统罕见疾病.已经报道CNF1在RTT的小鼠模型中具有有益效果。使用来自四个携带不同突变的患者的人RTT成纤维细胞,作为一个可靠的疾病模式,我们探索了细胞和分子机制,这可以作为CNF1诱导的RTT缺陷改善的基础。我们发现CNF1处理调节RTT成纤维细胞的RhoGTP酶活性,并诱导肌动蛋白细胞骨架的大量重组,主要是应力纤维。RTT成纤维细胞的线粒体显示出过灌注的形态,CNF1降低了线粒体质量,使线粒体动力学基本不变。从功能的角度来看,CNF1诱导RTT成纤维细胞线粒体膜电位去极化和AKT活化。鉴于线粒体质量控制在RTT中发生了改变,我们的结果提示通过线粒体自噬恢复,受损的线粒体被重新激活。这些效果可以基于CNF1在RTT中的有益效果。
The bacterial product CNF1, through its action on the Rho GTPases, is emerging as a modulator of crucial signalling pathways involved in selected neurological diseases characterized by mitochondrial dysfunctions. Mitochondrial impairment has been hypothesized to have a key role in paramount mechanisms underlying Rett syndrome (RTT), a severe neurologic rare disorder. CNF1 has been already reported to have beneficial effects in mouse models of RTT. Using human RTT fibroblasts from four patients carrying different mutations, as a reliable disease-in-a-dish model, we explored the cellular and molecular mechanisms, which can underlie the CNF1-induced amelioration of RTT deficits. We found that CNF1 treatment modulates the Rho GTPases activity of RTT fibroblasts and induces a considerable re-organization of the actin cytoskeleton, mainly in stress fibres. Mitochondria of RTT fibroblasts show a hyperfused morphology and CNF1 decreases the mitochondrial mass leaving substantially unaltered the mitochondrial dynamic. From a functional perspective, CNF1 induces mitochondrial membrane potential depolarization and activation of AKT in RTT fibroblasts. Given that mitochondrial quality control is altered in RTT, our results are suggestive of a reactivation of the damaged mitochondria removal via mitophagy restoration. These effects can be at the basis of the beneficial effects of CNF1 in RTT.