Mitochondrial iron accumulation in the heart promotes doxorubicin-induced cardiotoxicity.
Major finding: Mitochondrial iron accumulation in the heart promotes doxorubicin-induced cardiotoxicity.
Mechanism: Doxorubicin downregulates ABCB8 expression, resulting in decreased iron export and increased ROS.
Impact: Reduction of mitochondrial iron levels or increased iron export may prevent cardiac damage.
Treatment with the chemotherapeutic drug doxorubicin inhibits tumor growth but is associated with significant cardiotoxic side effects. Increased generation of reactive oxygen species (ROS) and altered regulation of iron homeostasis, as well as expression of topoisomerase 2β, have been suggested to contribute to doxorubicin-induced cardiomyopathy, but the mechanisms underlying this toxicity remain controversial. Ichikawa and colleagues found that doxorubicin treatment specifically triggered iron accumulation in the mitochondria of cardiomyocytes without affecting cytoplasmic or total cellular iron levels. In addition, mitochondrial iron levels were elevated in hearts of patients with doxorubicin-induced cardiomyopathy compared with normal hearts or hearts from patients with non–doxorubicin-associated cardiomyopathy. This preferential increase in mitochondrial iron levels was mediated in part by doxorubicin-dependent downregulation of ATP-binding cassette subfamily B member 8 (ABCB8), a transporter protein that promotes mitochondrial iron export. Depletion of ABCB8 enhanced the accumulation of mitochondrial iron and generation of ROS in response to doxorubicin, whereas ABCB8 overexpression diminished mitochondrial iron and ROS levels in cardiomyocytes in vitro, suggesting that this protein is cardioprotective. Consistent with this idea, transgenic overexpression of ABCB8 in vivo protected mice from doxorubicin-induced oxidative stress and cardiomyopathy and preserved mitochondrial structure and cardiomyocyte viability. Furthermore, in contrast with other iron chelators such as deferoxamine, dexrazoxane, a drug that limits cardiotoxicity in patients receiving doxorubicin, selectively decreased mitochondrial iron levels and improved cardiac function in mice treated with doxorubicin independent of topoisomerase 2β. These findings identify an important mediator of doxorubicin-triggered cardiotoxicity and support the development of therapeutic agents that specifically reduce mitochondrial iron levels in the heart or stimulate mitochondrial iron export.