TMEM175 mediates Lysosomal function and participates in neuronal injury induced by cerebral ischemia-reperfusion
TMEM175 mediates Lysosomal function and participates in neuronal injury induced by cerebral ischemia-reperfusion
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TMEM175介导溶酶体功能并参与脑缺血再灌注引起的神经元损伤
DOI：
10.1186/s13041-020-00651-z
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发表时间：
2020-08
期刊：
影响因子：
3.6
通讯作者：
Chen Gang
中科院分区：
文献类型：
--
作者：
Zhang Mengling;Lu Haifeng;Xie Xueshun;Shen Haitao;Li Xiang;Zhang Yunhai;Wu Jiang;Ni Jianqiang;Li Haiying;Chen Gang
作为清除受损蛋白质和受损细胞器的主要细胞器，溶酶体的功能对于维持长寿命神经元的细胞内稳态至关重要。稳定的酸性环境对于溶酶体执行其功能至关重要。 TMEM175已被确定为一种新的K+通道，该通道负责调节神经元中的溶酶体膜电位和pH稳定性。这项研究旨在了解TMEM175在脑缺血再灌注后神经元和神经元损伤的作用（I/R）。在体内的成年雄性Sprague-Dawley大鼠中建立了中脑动脉闭塞/再灌注（MCAO/R）模型，并将培养的神经元暴露于氧气 - 葡萄糖剥夺/Reoxygegenation（OGD/R），以模拟于Vitro中的中imimic Ischemia-Rechemia-Rechemia-Rechemia-Rechemia-Rechemia-Rechemia-Rechemia-Rechemia-Recreperfusion（I/R）。我们发现，脑I/R损伤后TMEM175的蛋白质水平降低，TMEM175过表达改善了MCAO/R诱导的脑细胞死亡和Vivo神经行为缺陷。此外，这些结果在培养的神经元中概括了。邻胺橙（AO）染色以及溶血感绿色DND-189，组织蛋白酶-B（CTSB）和组织蛋白酶-D（CTSD）活性，表明TMEM175缺乏通过影响溶酶体pH来抑制溶酶体的水解功能。相反，TMEM175上调逆转了OGD/R诱导的溶酶体功能障碍和培养神经元中线粒体积累受损。由脑I/R损伤诱导的TMEM175导致溶酶体pH稳定性受损，从而抑制溶酶体的水解功能。因此，受损线粒体的溶酶体依赖性降解被抑制，从而加剧了脑损伤。 TMEM175蛋白水平的外源上调可以逆转缺血 - 再灌注后的神经元溶酶体功能障碍。
As the main organelles for the clearance of damaged proteins and damaged organelles, the function of lysosomes is crucial for maintaining the intracellular homeostasis of long-lived neurons. A stable acidic environment is essential for lysosomes to perform their functions. TMEM175 has been identified as a new K+channel that is responsible for regulating lysosomal membrane potential and pH stability in neurons. This study aimed to understand the role of TMEM175 in lysosomal function of neurons and neuronal injury following cerebral ischemia-reperfusion (I/R). A middle-cerebral-artery occlusion/reperfusion (MCAO/R) model was established in adult male Sprague-Dawley rats in vivo, and cultured neurons were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic ischemia-reperfusion (I/R) injury in vitro. We found that the protein level of TMEM175 decreased after cerebral I/R injury and that TMEM175 overexpression ameliorated MCAO/R-induced brain-cell death and neurobehavioral deficits in vivo. Furthermore, these results were recapitulated in cultured neurons. Acridine orange (AO) staining, as well as LysoSensor Green DND-189, cathepsin-B (CTSB), and cathepsin-D (CTSD) activities, showed that TMEM175 deficiency inhibited the hydrolytic function of lysosomes by affecting lysosomal pH. In contrast, TMEM175 upregulation reversed OGD/R-induced lysosomal dysfunction and impaired mitochondrial accumulation in cultured neurons. TMEM175 deficiency induced by cerebral I/R injury leads to compromised lysosomal pH stability, thus inhibiting the hydrolytic function of lysosomes. Consequently, lysosomal-dependent degradation of damaged mitochondria is suppressed and thereby exacerbates brain damage. Exogenous up-regulation of TMEM175 protein level could reverse the neuronal lysosomal dysfunction after ischemia-reperfusion.
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影响因子：
5.3
作者：
通讯作者：
--
影响因子：
6.2
作者：
Ponomarev, Eugene D.;Veremeyko, Tatiana;Weiner, Howard L.
通讯作者：
Weiner, Howard L.
影响因子：
3.7
作者：
Huang C;Andres AM;Ratliff EP;Hernandez G;Lee P;Gottlieb RA
通讯作者：
Gottlieb RA
DOI：
10.1109/tcbb.2020.2993150
发表时间：
2020-05
期刊：
IEEE/ACM Transactions on Computational Biology and Bioinformatics
影响因子：
--
作者：
Hanif Yaghoobi;E. Babaei;B. Hussen;Ali Emami
通讯作者：
Hanif Yaghoobi;E. Babaei;B. Hussen;Ali Emami
影响因子：
3.4
作者：
Gao F;Wang FG;Lyu RR;Xue F;Zhang J;Huo R
通讯作者：
Huo R