Lysosomal basification and decreased autophagic flux in oxidatively stressed trabecular meshwork cells: implications for glaucoma pathogenesis.
Lysosomal basification and decreased autophagic flux in oxidatively stressed trabecular meshwork cells: implications for glaucoma pathogenesis.
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DOI：
10.4161/auto.23568
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发表时间：
2013-04
期刊：
影响因子：
13.3
通讯作者：
Liton PB
中科院分区：
文献类型：
--
作者：
Porter K;Nallathambi J;Lin Y;Liton PB
越来越多的证据表明，氧化损伤是导致传统的流出道组织无法维持适当的眼压水平的关键因素，从而增加了青光眼的风险，青光眼是一种迟发性疾病，是全球永久性失明的第二大原因。自噬正在成为抵抗包括氧化应激在内的各种应激源的一种重要的细胞生存机制。在这里，我们通过使用不同的方法(Lc3-I到Lc3-II周转率、tfLC3和细胞ID)监测在轻度慢性氧化应激的常压高氧模型下TM细胞自噬和自噬通量的诱导。我们的数据表明，在氧化应激的TM细胞中，MTOR介导的自噬激活和TFEB的核转位，以及自噬在SA-Glb1/SA-β-Gal的发生中的作用。然而，伴随着自噬途径的激活，在氧化应激条件下生长的TM细胞显示出组织蛋白酶(CTS)活性降低，溶酶体酸化和CTSB蛋白降解成熟减弱，导致自噬通量降低。我们认为，氧化应激诱导的自噬通量减少可能是导致细胞TM功能随年龄进行性丧失的因素之一，并参与了原发性开角型青光眼的发病机制。
Increasing evidence suggests oxidative damage as a key factor contributing to the failure of the conventional outflow pathway tissue to maintain appropriate levels of intraocular pressure, and thus increase the risk for developing glaucoma, a late-onset disease which is the second leading cause of permanent blindness worldwide. Autophagy is emerging as an essential cellular survival mechanism against a variety of stressors, including oxidative stress. Here, we have monitored, by using different methodologies (LC3-I to LC3-II turnover, tfLC3, and Cyto ID), the induction of autophagy and autophagy flux in TM cells subjected to a normobaric hyperoxic model of mild chronic oxidative stress. Our data indicate the MTOR-mediated activation of autophagy and nuclear translocation of TFEB in oxidatively stressed TM cells, as well as the role of autophagy in the occurrence of SA-GLB1/SA-β-gal. Concomitant with the activation of the autophagic pathway, TM cells grown under oxidative stress conditions displayed, however, reduced cathepsin (CTS) activities, reduced lysosomal acidification and impaired CTSB proteolytic maturation, resulting in decreased autophagic flux. We propose that diminished autophagic flux induced by oxidative stress might represent one of the factors leading to progressive failure of cellular TM function with age and contribute to the pathogenesis of primary open angle glaucoma.
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