Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. 
It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs 
through ROS production and possibly cellular iron accumulation. Here, we found 
that cardiotoxicity develops through the preferential accumulation of iron 
inside the mitochondria following doxorubicin treatment. In isolated 
cardiomyocytes, doxorubicin became concentrated in the mitochondria and 
increased both mitochondrial iron and cellular ROS levels. Overexpression of 
ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the 
hearts of transgenic mice decreased mitochondrial iron and cellular ROS and 
protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that 
attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron 
levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from 
patients with doxorubicin-induced cardiomyopathy had markedly higher 
mitochondrial iron levels than hearts from patients with other types of 
cardiomyopathies or normal cardiac function. These results suggest that the 
cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation 
and that reducing mitochondrial iron levels protects against doxorubicin-induced 
cardiomyopathy.