Doxorubicin (DOX) is a highly effective anti-neoplastic agent; however its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. We also observed significant reduction in FXN expression in DOX treated animals and H9C2 cardiomyoblast cell lines resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knock down (FXN-KD) stable cell lines constructed by lentiviral technology using shRNA. To better understand the cardioprotective role of FXN against DOX, we constructed frataxin over expressing cardiomyoblasts (FXN-OE) which displayed cardioprotection against mitochondrial iron accumulation, ROS formation and reduction of mitochondrial bioenergetics.