Protective effect of mitochondrial ferritin on cytosolic iron dysregulation induced by doxorubicin in HeLa cells.
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.
Molecular and Translational Medicine Department, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
Emiliano
E
Cocco
Vanessa
V
Porrini
Manuela
M
Derosas
Veronica
V
Nardi
Giorgio
G
Biasiotto
Federica
F
Maccarinelli
Isabella
I
Zanella
D000818:Animals; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*
D020011:Protective Agents; D004317:Doxorubicin; D007501:Iron