Overexpression of parkin rescues the defective mitochondrial phenotype and the increased apoptosis of Cockayne Syndrome A cells.
Overexpression of parkin rescues the defective mitochondrial phenotype and the increased apoptosis of Cockayne Syndrome A cells.
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DOI：
10.18632/oncotarget.9913
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发表时间：
2017-11-28
期刊：
影响因子：
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通讯作者：
Dogliotti E
中科院分区：
文献类型：
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作者：
Pascucci B;D'Errico M;Romagnoli A;De Nuccio C;Savino M;Pietraforte D;Lanzafame M;Calcagnile AS;Fortini P;Baccarini S;Orioli D;Degan P;Visentin S;Stefanini M;Isidoro C;Fimia GM;Dogliotti E
ERCC 8/CSA基因编码WD-40重复蛋白（CSA），其是E3-泛素连接酶/COP 9信号体复合物的一部分。当CSA突变时，会导致Cockayne综合征A组（CS-A），这是一种罕见的隐性早老性疾病，其特征是阳光敏感性和神经发育异常。CS-A细胞的特征包括ROS过度产生、氧化性基因组损伤的积累、线粒体功能障碍和可能导致神经退行性过程的细胞凋亡增加。在这项研究中，我们表明，CSA定位于线粒体，并专门与线粒体分裂蛋白动力相关蛋白（DRP 1），是超激活时，CSA是有缺陷的相互作用。CS-A细胞中增加的线粒体自噬不能抵消增加的裂变，从而导致碎片化线粒体的积累。然而，当线粒体受到线粒体毒素羰基氰间氯苯肼的挑战时，CS-A成纤维细胞与正常成纤维细胞一样有效地进行线粒体自噬，这表明该过程仍然可以靶向去除受损的线粒体。事实上，当通过在CSA缺陷细胞中过表达Parkin来增强基础线粒体自噬时，观察到功能失调的线粒体表型的显著拯救。重要的是，Parkin过表达不仅重新激活基础线粒体自噬，而且还通过显著减少CS-A细胞中线粒体处Bax的易位而发挥抗凋亡作用。这些发现为CSA在线粒体维护中的作用提供了新的机制见解，并可能为治疗方法开辟新的前景。
The ERCC8/CSA gene encodes a WD-40 repeat protein (CSA) that is part of a E3-ubiquitin ligase/COP9 signalosome complex. When mutated, CSA causes the Cockayne Syndrome group A (CS-A), a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. CS-A cells features include ROS hyperproduction, accumulation of oxidative genome damage, mitochondrial dysfunction and increased apoptosis that may contribute to the neurodegenerative process. In this study, we show that CSA localizes to mitochondria and specifically interacts with the mitochondrial fission protein dynamin-related protein (DRP1) that is hyperactivated when CSA is defective. Increased fission is not counterbalanced by increased mitophagy in CS-A cells thus leading to accumulation of fragmented mitochondria. However, when mitochondria are challenged with the mitochondrial toxin carbonyl cyanide m-chloro phenyl hydrazine, CS-A fibroblasts undergo mitophagy as efficiently as normal fibroblasts, suggesting that this process remains targetable to get rid of damaged mitochondria. Indeed, when basal mitophagy was potentiated by overexpressing Parkin in CSA deficient cells, a significant rescue of the dysfunctional mitochondrial phenotype was observed. Importantly, Parkin overexpression not only reactivates basal mitophagy, but plays also an anti-apoptotic role by significantly reducing the translocation of Bax at mitochondria in CS-A cells. These findings provide new mechanistic insights into the role of CSA in mitochondrial maintenance and might open new perspectives for therapeutic approaches.