Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration.
Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration.
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DOI：
10.1038/srep33830
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发表时间：
2016-09-22
影响因子：
4.6
通讯作者：
Ju WK
中科院分区：
文献类型：
--
作者：
Shim MS;Takihara Y;Kim KY;Iwata T;Yue BY;Inatani M;Weinreb RN;Perkins GA;Ju WK
视神经磷酸酶（OPTN）的突变与原发性开角型青光眼（POAG）和肌萎缩侧索硬化症的病理学有关。新出现的证据表明，OPTN突变涉及受损线粒体的积累和有缺陷的线粒体自噬。然而，OPTN E50 K突变在POAG视网膜神经节细胞（RGC）变性的致病线粒体机制中所起的作用仍然未知。我们在这里表明，E50 K的表达诱导线粒体分裂介导的线粒体降解和线粒体自噬在体内老年E50 K-tg小鼠的神经胶质层的轴突。虽然E50 K激活Bax途径和氧化应激，并触发动力学改变介导的线粒体降解和线粒体自噬在体外RGC胞体，它不影响运输动力学和线粒体在体外RGC轴突的分裂。这些结果强烈表明，E50 K与RGC变性中的线粒体功能障碍相关，与环境因素如衰老和/或氧化应激协同作用。
Mutations in optineurin (OPTN) are linked to the pathology of primary open angle glaucoma (POAG) and amyotrophic lateral sclerosis. Emerging evidence indicates that OPTN mutation is involved in accumulation of damaged mitochondria and defective mitophagy. Nevertheless, the role played by an OPTN E50K mutation in the pathogenic mitochondrial mechanism that underlies retinal ganglion cell (RGC) degeneration in POAG remains unknown. We show here that E50K expression induces mitochondrial fission-mediated mitochondrial degradation and mitophagy in the axons of the glial lamina of aged E50K−tg mice in vivo. While E50K activates the Bax pathway and oxidative stress, and triggers dynamics alteration-mediated mitochondrial degradation and mitophagy in RGC somas in vitro, it does not affect transport dynamics and fission of mitochondria in RGC axons in vitro. These results strongly suggest that E50K is associated with mitochondrial dysfunction in RGC degeneration in synergy with environmental factors such as aging and/or oxidative stress.
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