Zinc deficiency induces apoptosis via mitochondrial p53- and caspase-dependent pathways in human neuronal precursor cells |
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| Affiliation: | 1. Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA;2. Program in Neuroscience, Florida State University, Tallahassee, FL, USA;1. Institute of Problems of Chemical Physics, Russian Academy of Sciences, 141432 Chernogolovka, Moscow Region, Russian Federation;2. A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow, Russian Federation;1. Institute of Chemical Materials, China Academy of Engineering Physics, Mianyang 621900, People’s Republic of China;2. Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2;3. Center for Crystal Research and Development, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, People’s Republic of China;1. Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, Jiangsu Collaborative Innovation Center for Atmospheric Environment & Equipment Technology, School of Environmental Science and Engineering, Nanjing University of Information Science & Technology, Nanjing 210044, Jiangsu, P. R. China;2. Institute of Chemical Materials, Chinese Academy of Engineering Physics, Mianyang 621999, Sichuan, P. R. China |
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| Abstract: | Previous studies have shown that zinc deficiency leads to apoptosis of neuronal precursor cells in vivo and in vitro. In addition to the role of p53 as a nuclear transcription factor in zinc deficient cultured human neuronal precursors (NT-2), we have now identified the translocation of phosphorylated p53 to the mitochondria and p53-dependent increases in the pro-apoptotic mitochondrial protein BAX leading to a loss of mitochondrial membrane potential as demonstrated by a 25% decrease in JC-1 red:green fluorescence ratio. Disruption of mitochondrial membrane integrity was accompanied by efflux of the apoptosis inducing factor (AIF) from the mitochondria and translocation to the nucleus with a significant increase in reactive oxygen species (ROS) after 24 h of zinc deficiency. Measurement of caspase cleavage, mRNA, and treatment with caspase inhibitors revealed the involvement of caspases 2, 3, 6, and 7 in zinc deficiency-mediated apoptosis. Down-stream targets of caspase activation, including the nuclear structure protein lamin and polyADP ribose polymerase (PARP), which participates in DNA repair, were also cleaved. Transfection with a dominant-negative p53 construct and use of the p53 inhibitor, pifithrin-μ, established that these alterations were largely dependent on p53. Together these data identify a cascade of events involving mitochondrial p53 as well as p53-dependent caspase-mediated mechanisms leading to apoptosis during zinc deficiency. |
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| Keywords: | Zinc Apoptosis Caspase p53 NT-2 |
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