Mitochondrial Ferritin Is a Hypoxia-Inducible Factor 1α-Inducible Gene That Protects from Hypoxia-Induced Cell Death in Brain

Abstract

<b><i>Aims:</i></b> 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. <b><i>Results:</i></b> 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 <i>FTMT</i> 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. <b><i>Innovation:</i></b> In the absence of FtMt, this catalytic metal excess catalyzes the production of cytotoxic reactive oxygen species. <b><i>Conclusion:</i></b> Thus, the cell ability to increase expression of FtMt during hypoxia may be a skill to avoid tissue damage derived from oxygen limitation.