Biphasic regulation of lysosomal exocytosis by oxidative stress.
Biphasic regulation of lysosomal exocytosis by oxidative stress.
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DOI：
10.1016/j.ceca.2016.08.002
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发表时间：
2016-11
期刊：
影响因子：
4
通讯作者：
Kiselyov K
中科院分区：
文献类型：
--
作者：
Ravi S;Peña KA;Chu CT;Kiselyov K
氧化应激导致包括缺血性中风和神经退行性疾病在内的许多疾病中的细胞死亡。更好地了解细胞如何从氧化应激中恢复可能会导致更好地治疗中风和其他疾病。最近在几个模型中获得的证据将溶酶体胞吐过程与蛋白质聚集体和有毒金属的清除联系在一起。在正常或病理条件下，调节溶酶体胞吐的机制才刚刚开始出现。在这里，我们提供了氧化应激对溶酶体胞吐的双相效应的证据。用溶酶体酶β-己糖胺酶(β-Hex)胞外水平测定溶酶体胞吐作用。低水平或氧化应激刺激溶酶体胞吐，但在高水平抑制它。溶酶体离子通道TRPML1的缺失消除了低水平氧化应激的刺激作用。氧化应激的抑制作用似乎针对由细胞外钙离子驱动的溶酶体胞吐作用的成分。我们认为，虽然适度的氧化应激通过刺激溶酶体胞吐促进细胞修复，但在高水平的氧化应激具有双重病理效应：它直接导致细胞损伤，并通过抑制溶酶体胞吐而损害损伤修复。利用这些适应性机制可能指向对涉及氧化蛋白毒性或金属毒性的疾病的药物干预。
Oxidative stress drives cell death in a number of diseases including ischemic stroke and neurodegenerative diseases. A better understanding of how cells recover from oxidative stress is likely to lead to better treatments for stroke and other diseases. The recent evidence obtained in several models ties the process of lysosomal exocytosis to the clearance of protein aggregates and toxic metals. The mechanisms that regulate lysosomal exocytosis, under normal or pathological conditions, are only beginning to emerge. Here we provide evidence for the biphasic effect of oxidative stress on lysosomal exocytosis. Lysosomal exocytosis was measured using the extracellular levels of the lysosomal enzyme beta-hexosaminidase (β-hex). Low levels or oxidative stress stimulated lysosomal exocytosis, but inhibited it at high levels. Deletion of the lysosomal ion channel TRPML1 eliminated the stimulatory effect of low levels of oxidative stress. The inhibitory effects of oxidative stress appear to target the component of lysosomal exocytosis that is driven by extracellular Ca2+. We propose that while moderate oxidative stress promotes cellular repair by stimulating lysosomal exocytosis, at high levels oxidative stress has a dual pathological effect: it directly causes cell damage and impairs damage repair by inhibiting lysosomal exocytosis. Harnessing these adaptive mechanisms may point to pharmacological interventions for diseases involving oxidative proteotoxicity or metal toxicity.
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DOI：
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发表时间：
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期刊：
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影响因子：
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