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Protective effect of mitochondrial ferritin on cytosolic iron dysregulation induced by doxorubicin in HeLa cells

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Abstract

Doxorubicin (DOX) is an anticancer drug with cardiotoxic side effects mostly caused by iron homeostasis dysregulation. Mitochondria are involved in iron trafficking and mitochondrial ferritin (FtMt) was shown to provide protection against cellular iron imbalance. Therefore, we hypothesized that FtMt overexpression could limit DOX effects on iron homeostasis. Heart’s homogenates of DOX-treated C57BL/6 mice were analyzed for cytosolic and mitochondrial iron-related proteins’ expression and activity, revealing high cytosolic ferritin and ferritin-bound iron, low transferrin-receptor 1 and a strong hepcidin upregulation. Mitochondrial iron-related proteins (aconitase, succinate-dehydrogenase, frataxin) seemed, however, unaffected, although a partial inactivation of superoxide dismutase 2 was detected. Importantly, the ectopic expression of FtMt in human HeLa cells partially reverted DOX-induced iron imbalance. Our results, while confirming DOX effects on iron homeostasis, demonstrate that DOX affects more cytosolic than mitochondrial iron metabolism both in murine hearts and human HeLa cells and that FtMt overexpression is able to prevent most of these effects in HeLa cells.

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Acknowledgments

Funded by University of Brescia (Fondi ex 60 % to I.Z.). We thank Dr. Sonia Levi (San Raffaele Scientific Institute, Milan, Italy) and Dr. Franco Taroni (Istituto Neurologico Carlo Besta, Milan, Italy) for supplying MT53 cells and antibodies to murine FTH and FTL and to frataxin.

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Author notes

  1. Emiliano Cocco

    Present address: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA

  2. Manuela Derosas

    Present address: IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Bergamo, Italy

Authors and Affiliations

  1. Molecular and Translational Medicine Department, University of Brescia, Viale Europa 11, 25123, Brescia, Italy

    Emiliano Cocco, Vanessa Porrini, Manuela Derosas, Veronica Nardi, Giorgio Biasiotto, Federica Maccarinelli & Isabella Zanella

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  1. Emiliano Cocco
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  2. Vanessa Porrini
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  3. Manuela Derosas
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  4. Veronica Nardi
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  5. Giorgio Biasiotto
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  6. Federica Maccarinelli
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  7. Isabella Zanella
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Corresponding author

Correspondence to Isabella Zanella.

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Emiliano Cocco and Vanessa Porrini have contributed equally to this work.

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Cocco, E., Porrini, V., Derosas, M. et al. Protective effect of mitochondrial ferritin on cytosolic iron dysregulation induced by doxorubicin in HeLa cells. Mol Biol Rep 40, 6757–6764 (2013). https://doi.org/10.1007/s11033-013-2792-z

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  • DOI: https://doi.org/10.1007/s11033-013-2792-z

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