Oxygen Glucose Deprivation (OGD)/Re-Oxygenation-Induced In Vitro Neuronal Cell Death Involves Mitochondrial Cyclophilin-
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ORIGINAL PAPER
Oxygen Glucose Deprivation (OGD)/Re-Oxygenation-Induced In Vitro Neuronal Cell Death Involves Mitochondrial Cyclophilin-D/P53 Signaling Axis Li-Ping Zhao • Chao Ji • Pei-Hua Lu Chen Li • Bo Xu • Hong Gao
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Received: 30 September 2012 / Revised: 5 December 2012 / Accepted: 3 January 2013 / Published online: 16 January 2013 Ó Springer Science+Business Media New York 2013
Abstract 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
Li-Ping Zhao and Chao Ji two authors contribute equally. L.-P. Zhao 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 C. Ji Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210024, Jiangsu, China P.-H. Lu Department of General Surgery, Wuxi People’s Hospital of Nanjing Medical University, No. 299, Qingyang Road, Wuxi 214023, Jiangsu Province, China C. Li Department of Gastroenterology, Xuzhou Chinese Medical Hospital Affiliated to Nanjing University of Chinese Medicine, Xuzhou, Jiangsu Province, China B. Xu H. Gao (&) Department of Anesthesiology, Wuxi People’s Hospital of Nanjing Medical University, No 299, Qingyang Road, Wuxi 214023, Jiangsu Province, China e-mail: [email protected]
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-oxygenationinduced 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. Keywords Oxygen glucose deprivation Cyclophilin D p53 and neuronal death Abbreviations OGD Oxygen glucose deprivation Cyp-D Cyclophilin D CsA Cyclosporine A H2O2 Hydrogen peroxide LDH Lactate dehydrogenase mPTP Mitochondrial permeability transition pore ROS Reactive oxygen species NAC n-Acetyl cysteine GFP Green fluorescence protein MEFs Mouse embryonic fibroblasts ANT Adenine nucleotide translocase VDAC Voltage-dependent anion transporter
Introduction The involvement of oxidative stress in oxygen glucose deprivation (OGD)/re-oxygenation-induced in vitro neuronal cell death has been well established [1, 2]. Serve or sustained ODG ([1 h) is known to disrupt mitochondrial functions
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