Qiong Wu1,2,3,4, Wen-Shuang Wu1,3,4, Lin Su1, Xin Zheng1, Wen-Yue Wu1, Paolo Santambrogio2, Yu-Jing Gou1, Qian Hao1, Pei-Na Wang1, Ya-Ru Li1, Bao-Lu Zhao1, Guangjun Nie5, Sonia Levi2,6, Yan-Zhong Chang1. 1. 1 Laboratory of Molecular Iron Metabolism, The Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University , Shijiazhuang, China . 2. 2 Division of Neuroscience, San Raffaele Scientific Institute , Milano, Italy . 3. 3 College of Basic Medicine, Hebei University of Chinese Medicine , Shijiazhuang, China . 4. 4 Department of Clinical Laboratory, The Third Hospital of Hebei Medical University , Shijiazhuang, China . 5. 5 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology , Beijing, China . 6. 6 Vita-Salute San Raffaele University , Milano, Italy .
Abstract
Aims: Mitochondrial ferritin (protein [FtMt]) is preferentially expressed in cell types of high metabolic activity and oxygen consumption, which is consistent with its role of sequestering iron and preventing oxygen-derived redox damage. As of yet, the mechanisms of FtMt regulation and the protection FtMt affords remain largely unknown. Results: Here, we report that hypoxia-inducible factor 1α (HIF-1α) can upregulate FtMt expression. We verify one functional hypoxia-response element (HRE) in the positive regulatory region and two HREs possessing HIF-1α binding activity in the minimal promoter region of the human FTMT gene. We also demonstrate that FtMt can alleviate hypoxia-induced brain cell death by sequestering uncommitted iron, whose levels increase with hypoxia in these cells. Innovation: In the absence of FtMt, this catalytic metal excess catalyzes the production of cytotoxic reactive oxygen species. Conclusion: Thus, the cell ability to increase expression of FtMt during hypoxia may be a skill to avoid tissue damage derived from oxygen limitation.
Aims: Mitochondrial ferritin (protein [FtMt]) is preferentially expressed in cell types of high metabolic activity and oxygen consumption, which is consistent with its role of sequestering iron and preventing oxygen-derived redox damage. As of yet, the mechanisms of FtMt regulation and the protection FtMt affords remain largely unknown. Results: Here, we report that hypoxia-inducible factor 1α (HIF-1α) can upregulate FtMt expression. We verify one functional hypoxia-response element (HRE) in the positive regulatory region and two HREs possessing HIF-1α binding activity in the minimal promoter region of the humanFTMT gene. We also demonstrate that FtMt can alleviate hypoxia-induced brain cell death by sequestering uncommitted iron, whose levels increase with hypoxia in these cells. Innovation: In the absence of FtMt, this catalytic metal excess catalyzes the production of cytotoxic reactive oxygen species. Conclusion: Thus, the cell ability to increase expression of FtMt during hypoxia may be a skill to avoid tissue damage derived from oxygen limitation.