Xu Qin-Qin, Xiao Feng-Jun, Sun Hui-Yan, Shi Xue-Feng, Wang Hua, Yang Yue-Feng, Li Yu-Xiang, Wang Li-Sheng, Ge Ri-Li
High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining, 810001, PR China; Qinghai Provincial People's Hospital, Xining, PR China.
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
Biochem Biophys Res Commun. 2016 Mar 18;471(4):459-65. doi: 10.1016/j.bbrc.2016.02.053. Epub 2016 Feb 17.
Hypoxia provokes metabolism misbalance, mitochondrial dysfunction and oxidative stress in both human and animal cells. However, the mechanisms which hypoxia causes mitochondrial dysfunction and energy metabolism misbalance still remain unclear. In this study, we presented evidence that mitochondrial phosphatase Ptpmt1 is a hypoxia response molecule that regulates cell proliferation, survival and glucose metabolism in human erythroleukemia TF-1 cells. Exposure to hypoxia or DFO treatment results in upregulation of HIF1-α, HIF-2α and Ptpmt1. Only inhibition of HIF-2α by shRNA transduction reduces Ptpmt1 expression in TF-1 cells under hypoxia. Ptpmt1 inhibitor suppresses the growth and induces apoptosis of TF-1 cells. Furthermore, we demonstrated that Ptpmt1 inhibition reduces the Glut1 and Glut3 expression and decreases the glucose consumption in TF-1 cells. In additional, Ptpmt1 knockdown also results in the mitochondrial dysfunction determined by JC1 staining. These results delineate a key role for HIF-2α-induced Ptpmt1 upregulation in proliferation, survival and glucose metabolism of erythroleukemia cells. It is indicated that Ptpmt1 plays important roles in hypoxia-induced cell metabolism and mitochondrial dysfunction.
缺氧会引发人和动物细胞中的代谢失衡、线粒体功能障碍及氧化应激。然而，缺氧导致线粒体功能障碍和能量代谢失衡的机制仍不清楚。在本研究中，我们提供了证据表明线粒体磷酸酶Ptpmt1是一种缺氧反应分子，可调节人红白血病TF-1细胞的增殖、存活及葡萄糖代谢。暴露于缺氧环境或经去铁胺（DFO）处理会导致缺氧诱导因子1α（HIF1-α）、缺氧诱导因子2α（HIF-2α）和Ptpmt1上调。仅通过短发夹RNA（shRNA）转导抑制HIF-2α可降低缺氧条件下TF-1细胞中Ptpmt1的表达。Ptpmt1抑制剂可抑制TF-1细胞的生长并诱导其凋亡。此外，我们证明抑制Ptpmt1会降低TF-1细胞中葡萄糖转运蛋白1（Glut1）和葡萄糖转运蛋白3（Glut3）的表达，并减少葡萄糖消耗。另外，通过JC1染色确定，敲低Ptpmt1也会导致线粒体功能障碍。这些结果表明，HIF-2α诱导的Ptpmt1上调在红白血病细胞的增殖、存活和葡萄糖代谢中起关键作用。表明Ptpmt1在缺氧诱导的细胞代谢和线粒体功能障碍中起重要作用。
