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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2161-2167.
Prepublished online as a Blood First Edition Paper on November 2, 2004; DOI 10.1182/blood-2004-07-2722.
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Submitted July 15, 2004
Accepted October 25, 2004
Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis
Guangjun Nie, Alex D Sheftel, Sangwon F Kim, and Prem Ponka*
Departments of Physiology and Medicine, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, QC, Canada
* Corresponding author; email: prem.ponka{at}mcgill.ca.
Cytosolic ferritin sequesters and stores iron and, consequently, protects cells against iron-mediated free radical damage. However, the function of the newly discovered mitochondrial ferritin (MtFt) is unknown. To examine the role of MtFt in cellular iron metabolism, we established a cell line that stably overexpresses mouse MtFt under the control of a tetracycline-responsive promoter. The overexpression of MtFt caused a dose-dependent iron deficiency in the cytosol that was revealed by increased RNA-binding activity of iron regulatory proteins (IRPs) along with an increase in transferrin receptor levels and decrease in cytosolic ferritin. Consequently, the induction of MtFt resulted in a dramatic increase in cellular iron uptake from transferrin, most of which was incorporated into MtFt. The induction of MtFt caused a shift of iron from cytosolic ferritin to MtFt. In addition, iron inserted into MtFt was less available for chelation than that in cytosolic ferritin and the expression of MtFt was associated with decreased mitochondrial and cytosolic aconitase activities, the latter being in consistent with the increase in IRP binding activity. In conclusion, our results indicate that overexpression of MtFt causes a dramatic change in intracellular iron homeostasis and that shunting iron to MtFt likely limits its availability for active iron proteins.
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