Long-isoform NRF1 protects against arsenic cytotoxicity in mouse bone marrow-derived mesenchymal stem cells by suppressing mitochondrial ROS and facilitating arsenic efflux
Long-isoform NRF1 protects against arsenic cytotoxicity in mouse bone marrow-derived mesenchymal stem cells by suppressing mitochondrial ROS and facilitating arsenic efflux
复制标题
长异构体 NRF1 通过抑制线粒体 ROS 和促进砷外流来保护小鼠骨髓来源的间充质干细胞免受砷细胞毒性
DOI：
10.1016/j.taap.2020.115251
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发表时间：
2020-11-15
影响因子：
3.8
通讯作者：
Xu, Yuanyuan
中科院分区：
文献类型：
--
作者：
Lou, Bin;Hu, Yuxin;Xu, Yuanyuan
众所周知，急性接触砷会导致骨髓抑制并导致贫血，其中骨髓微环境中细胞（例如间充质干细胞（MSC））的功能障碍至关重要。然而，间充质干细胞对砷挑战的反应机制尚不完全清楚。在本研究中，我们研究了核因子红细胞2相关因子（NRF）1（NRF1）（抗氧化反应中著名的主调节因子NRF2的姐妹成员）在亚砷酸盐诱导的小鼠骨髓间充质干细胞（mBM-MSCs）细胞毒性中的作用。我们发现亚砷酸盐暴露会导致长亚型 NRF1 (L-NRF1) 的蛋白质水平显着增加。虽然亚砷酸盐在 mRNA 水平诱导短亚型 NRF1 (S-NRF1)，但其蛋白水平没有明显改变。沉默 L-Nrf1 会使细胞对亚砷酸盐诱导的细胞毒性敏感。在亚砷酸盐暴露的条件下，LNrf1沉默的mBM-MSC表现出砷外流减少，砷转运蛋白ATP结合盒亚家族C成员4（ABCC4）的表达减少，以及NRF2介导的抗氧化防御受损，线粒体活性氧（mtROS）水平升高。在 L-Nrf1 沉默的 mBMMSC 中，特定的 mtROS 清除剂（Mito-quinone）可减轻亚砷酸盐诱导的细胞凋亡。综上所述，这些发现表明，L-NRF1 除了促进细胞砷外流外，还通过抑制 mtROS 来保护 mBM-MSC 免受亚砷酸盐诱导的细胞毒性。
Acute exposure to arsenic is known to cause bone marrow depression and result in anemia, in which the dusfunction of cells in the bone marrow niche such as mesenchymal stem cells (MSCs) is vital. However, the mechanism underlying response of MSCs to arsenic challange is not fully understood. In the present study, we investigated the role of nuclear factor erythroid 2-related factor (NRF) 1 (NRF1), a sister member of the wellknown master regulator in antioxidative response NRF2, in arsenite-induced cytotoxicity in mouse bone marrowderived MSCs (mBM-MSCs). We found that arsenite exposure induced significant increase in the protein level of long-isoform NRF1 (L-NRF1). Though short-isoform NRF1 (S-NRF1) was induced by arsenite at mRNA level, its protein level was not obviously altered. Silencing L-Nrf1 sensitized the cells to arsenite-induced cytotoxicity. LNrf1-silenced mBM-MSCs showed decreased arsenic efflux with reduced expression of arsenic transporter ATPbinding cassette subfamily C member 4 (ABCC4), as well as compromised NRF2-mediated antioxidative defense with elevated level of mitochondrial reactive oxygen species (mtROS) under arsenite-exposed conditions. A specific mtROS scavenger (Mito-quinone) alleviated cell apoptosis induced by arsenite in L-Nrf1-silenced mBMMSCs. Taken together, these findings suggest that L-NRF1 protects mBM-MSCs from arsenite-induced cytotoxicity via suppressing mtROS in addition to facilitating cellular arsenic efflux.