细胞凋亡
癌症研究
线粒体
蛋白激酶B
张力素
生物
活性氧
自噬
PI3K/AKT/mTOR通路
作者
Xiangyu Xu,Yu Cui,Congqin Li,Yuyang Wang,Jing Cheng,Song-Feng Chen,Jiangdong Sun,Jinyang Ren,Xujin Yao,Jingchen Gao,Xiaohong Huang,Qi Wan,Qiang Wang
标识
DOI:10.1007/s12035-021-02459-x
摘要
SET domain protein 3 (SETD3) is an actin-specific methyltransferase, a rare post-translational modification with limited known biological functions. Till now, the function of SETD3 in cerebral ischemia-reperfusion (I/R)-induced injury remains unknown. Here, we show that the protein level of SETD3 is decreased in rat neurons after cerebral I/R injury. SETD3 promotes neuronal survival after both glucose and oxygen deprivation/reoxygenation (OGD/R) and cerebral I/R injury, and knockdown of SETD3 increases OGD/R-induced neuronal death. We further show that OGD/R-induced downregulation of SETD3 leads to the decrease of cellular ATP level, the reduction of mitochondrial electric potential and the increase of ROS production, thereby promoting mitochondrial dysfunction. We found that SETD3 reduction-induced mitochondrial dysfunction is mediated by the suppression of actin polymerization after OGD/R. Furthermore, we demonstrate that I/R-induced upregulation of PTEN leads to the downregulation of SETD3, and suppressing PTEN protects against ischemic neuronal death through downregulation of SETD3 and enhancement of actin polymerization. Together, this study provides the first evidence suggesting that I/R-induced downregulation of SETD3 mediates PTEN upregulation-induced ischemic neuronal death through downregulation of SETD3 and subsequent suppression of actin polymerization. Thus, upregulating SETD3 is a potential approach for the development of ischemic stroke therapy.
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