UBIAD1 protects against oxygen-glucose deprivation/reperfusion-induced multiple subcellular organelles injury through PI3K/AKT pathway in N2A cells
UBIAD1 protects against oxygen-glucose deprivation/reperfusion-induced multiple subcellular organelles injury through PI3K/AKT pathway in N2A cells
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DOI：
10.1002/jcp.26602
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发表时间：
2018-09-01
影响因子：
5.6
通讯作者：
Hu, Zhiping
中科院分区：
文献类型：
--
作者：
Huang, Yan;Hu, Zhiping
脑缺血/再灌注损伤在缺血性卒中后多亚细胞器损伤的发生发展中起重要作用。UBIAD 1最初被发现是一种潜在的肿瘤抑制蛋白。最近，对UBIAD 1的分析表明，它是一种异戊烯基转移酶，用于非线粒体辅酶Q10和维生素K2的生产。此外，UBIAD 1已定位于多个亚细胞器。尤其是UBIAD 1在氧化应激、细胞凋亡和增殖、胆固醇和脂质代谢的调节中发挥重要作用，与脑缺血/再灌注机制密切相关。然而，UBIAD 1对脑缺血/再灌注诱导的损伤的潜在作用机制仍不清楚。本研究采用经典的氧糖剥夺再灌注（OGD/R）损伤小鼠N2 A细胞，观察UBIAD 1对缺血/再灌注诱导的多种亚细胞器损伤的影响。OGD/R后小鼠N2 A细胞中UBIAD 1的表达降低。UBIAD 1在N2 a细胞中表现出多亚细胞器共定位，包括在线粒体、内质网和高尔基体中。UBIAD 1的过表达显著地防止了OGD/R诱导的细胞死亡。UBIAD 1过表达也减弱了OGD/R诱导的线粒体断裂和功能障碍，并介导了凋亡相关蛋白的水平。此外，我们观察到UBIAD 1的过表达改善了OGD/R诱导的片段化，并降低了内质网和高尔基体中氧化应激相关蛋白的表达水平。此外，UBIAD 1的神经保护作用与PI 3 K/AKT通路相关，这是使用PI 3 K抑制剂LY 294002和perifosion证明的。总的来说，这些发现确定了UBIAD 1通过PI 3 K/AKT途径保护OGD/R诱导的多个亚细胞器损伤。
Cerebral ischemia/reperfusion-induced injury plays a significant role in the development of multi-subcellular organelles injury after ischemic stroke. UBIAD1 was discovered originally as a potential tumor suppressor protein. Recently, analysis of UBIAD1 has indicated it is a prenyltransferase enzyme for both non-mitochondrial CoQ10 and vitamin K2 production. Further, UBIAD1 has been localized to multiple subcellular organelles. Particularly, UBIAD1 plays an important role in the regulation of oxidative stress, apoptosis and cell proliferation, cholesterol and lipid metabolism, which was closely associated with the cerebral ischemic/reperfusion mechanism. However, the mechanism underlying effects of UBIAD1 on cerebral ischemia/reperfusion-induced injury remains largely unknown. We aimed to investigate the effects of UBIAD1 on ischemia/reperfusion-induced multiple subcellular organelles injury in vitro, mouse N2A cells were subjected to a classical oxygen-glucose deprivation and reperfusion (OGD/R) insult. The expression of UBIAD1 was reduced in mouse N2A cells after OGD/R. UBIAD1 exhibits multi-subcellular organelles co-localization in N2a cells, including in the mitochondria, endoplasmic reticulum, and Golgi apparatus. The over-expression of UBIAD1 significantly protects against OGD/R-induced cell death. UBIAD1 over-expression also attenuated OGD/R-induced mitochondrial fragmentation and dysfunction and mediated the level of apoptosis-associated protein. Moreover, we observed that the over-expression of UBIAD1 ameliorated OGD/R-induced fragmentation and reduced the level of oxidative stress-related protein expression in both the endoplasmic reticulum and Golgi apparatus. Besides, the neuroprotective effect of UBIAD1 was correlated with the PI3K/AKT pathway, which was demonstrated using the PI3K inhibitor LY294002 and perifosion. Collectively, these findings identified that UBIAD1 protects against OGD/R-induced multiple subcellular organelles injury through PI3K/AKT Pathway.