State Key Laboratory of Reproductive Medicine, Department of Anesthesiology, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
Neurochem Res. 2013 Apr;38(4):705-13. doi: 10.1007/s11064-013-0968-5. Epub 2013 Jan 16.
Oxidative stress-induced neuronal cell death requires opening of the mitochondrial permeability transition pore. P53 mitochondrial translocation and association with Cyclophilin D (Cyp-D) is required for the pore opening. Here we tested this signaling axis in oxygen glucose deprivation (OGD)/re-oxygenation-induced in vitro neuronal death. Using mitochondrion immunoprecipitation, we found that p53 translocated to mitochondrion and associated with Cyp-D in SH-SY5Y cells exposed to (OGD)/re-oxygenation. Disruption of this complex by Cyp-D inhibitor Cyclosporine A (CsA), or by Cyp-D or p53 deficiency, significantly inhibited OGD/re-oxygenation-induced apoptosis-independent cell death. Conversely, over-expression of Cyp-D in SH-SY5Y cells caused spontaneous cell death, and these cells were more vulnerable to OGD/re-oxygenation. Finally, CsA or Cyp-D RNAi suppressed OGD/re-oxygenation-induced neuronal cell death in primary cultures. Together, our study suggests that OGD/re-oxygenation-induced in vitro cell death involves a mitochondrial Cyp-D/p53 signaling axis.
氧化应激诱导的神经元细胞死亡需要线粒体通透性转换孔的开放。p53 线粒体易位并与亲环素 D（Cyp-D）结合是孔开放所必需的。在这里，我们在体外氧葡萄糖剥夺（OGD）/再氧合诱导的神经元死亡中测试了这个信号轴。使用线粒体免疫沉淀，我们发现 p53 在暴露于（OGD）/再氧合的 SH-SY5Y 细胞中转位到线粒体并与 Cyp-D 结合。Cyp-D 抑制剂环孢菌素 A（CsA）、Cyp-D 或 p53 缺陷的破坏，显著抑制 OGD/再氧合诱导的凋亡非依赖性细胞死亡。相反，Cyp-D 在 SH-SY5Y 细胞中的过表达导致自发性细胞死亡，这些细胞对 OGD/再氧合更为敏感。最后，CsA 或 Cyp-D RNAi 抑制原代培养物中 OGD/再氧合诱导的神经元细胞死亡。总之，我们的研究表明，OGD/再氧合诱导的体外细胞死亡涉及线粒体 Cyp-D/p53 信号轴。
