Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Ferrara, Italy.
Plants for Human Health Institute, Animal Science Dept., North Carolina State University, Kannapolis, NC, USA.
Arch Biochem Biophys. 2021 Mar 30;700:108790. doi: 10.1016/j.abb.2021.108790. Epub 2021 Feb 4.
Rett Syndrome (RTT) is a rare neurodevelopmental disorder caused in the 95% of cases by mutations in the X-linked MECP2 gene, affecting almost exclusively females. While the genetic basis of RTT is known, the exact pathogenic mechanisms that lead to the broad spectrum of symptoms still remain enigmatic. Alterations in the redox homeostasis have been proposed among the contributing factors to the development and progression of the syndrome. Mitochondria appears to play a central role in RTT oxidative damage and a plethora of mitochondrial defects has already been recognized. However, mitochondrial dynamics and mitophagy, which represent critical pathways in regulating mitochondrial quality control (QC), have not yet been investigated in RTT. The present work showed that RTT fibroblasts have networks of hyperfused mitochondria with morphological abnormalities and increased mitochondrial volume. Moreover, analysis of mitophagic flux revealed an impaired PINK1/Parkin-mediated mitochondrial removal associated with an increase of mitochondrial fusion proteins Mitofusins 1 and 2 (MFN1 and 2) and a decrease of fission mediators including Dynamin related protein 1 (DRP1) and Mitochondrial fission 1 protein (FIS1). Finally, challenging RTT fibroblasts with FCCP and 2,4-DNP did not trigger a proper apoptotic cell death due to a defective caspase 3/7 activation. Altogether, our findings shed light on new aspects of mitochondrial dysfunction in RTT that are represented by defective mitochondrial QC pathways, also providing new potential targets for a therapeutic intervention aimed at slowing down clinical course and manifestations in the affected patients.
雷特综合征（RTT）是一种罕见的神经发育障碍，95%的病例是由 X 连锁的 MECP2 基因突变引起的，几乎只影响女性。虽然 RTT 的遗传基础已经为人所知，但导致其广泛症状的确切发病机制仍然神秘莫测。氧化还原平衡的改变被认为是导致该综合征发生和发展的因素之一。线粒体似乎在 RTT 氧化损伤中起核心作用，已经认识到许多线粒体缺陷。然而，线粒体动力学和自噬，作为调节线粒体质量控制（QC）的关键途径，尚未在 RTT 中进行研究。本工作表明，RTT 成纤维细胞存在超融合线粒体网络，具有形态异常和线粒体体积增加。此外，对自噬通量的分析显示，PINK1/Parkin 介导的线粒体清除受损与线粒体融合蛋白 Mitofusins 1 和 2（MFN1 和 2）增加和分裂介体包括动力相关蛋白 1（DRP1）和线粒体分裂 1 蛋白（FIS1）减少有关。最后，用 FCCP 和 2,4-DNP 挑战 RTT 成纤维细胞不会引发适当的细胞凋亡，因为 caspase 3/7 的激活受损。总之，我们的研究结果揭示了 RTT 中线粒体功能障碍的新方面，表现为线粒体 QC 途径缺陷，并为旨在减缓受影响患者的临床病程和表现的治疗干预提供了新的潜在靶点。
