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 DOXtreated
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, succinatedehydrogenase,
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