Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation
Yoshihiko Ichikawa, Mohsen Ghanefar, Marina Bayeva, Rongxue Wu, Arineh Khechaduri, Sathyamangla V. Naga Prasad, R. Kannan Mutharasan, Tejaswitha Jairaj Naik, Hossein Ardehali
Yoshihiko Ichikawa, Mohsen Ghanefar, Marina Bayeva, Rongxue Wu, Arineh Khechaduri, Sathyamangla V. Naga Prasad, R. Kannan Mutharasan, Tejaswitha Jairaj Naik, Hossein Ardehali
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Research Article Cardiology

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

Abstract

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.

Authors

Yoshihiko Ichikawa, Mohsen Ghanefar, Marina Bayeva, Rongxue Wu, Arineh Khechaduri, Sathyamangla V. Naga Prasad, R. Kannan Mutharasan, Tejaswitha Jairaj Naik, Hossein Ardehali

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Figure 9

Cytotoxicity of DOX through mitochondrial iron is independent of the Top-2β pathway.

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Cytotoxicity of DOX through mitochondrial iron is independent of the Top...
(A) Western blot analysis of Top-2β and ABCB8 expression in NRCMs treated with Top-2β or control siRNA, showing efficient reduction in Top-2β protein with siRNA treatment but no change in ABCB8 protein level. (B) Mitochondrial and (C) cytosolic iron levels determined by quantification of 55Fe radioactivity in NRCMs with Top-2β or control siRNA (n = 4). (D–F) Western blot analysis of Top-2β protein (D) in NRCMs treated with 10 μM DOX with or without 200 μM DXZ or 200 μM DFO for 16 hours, (E) in NRCMs with adenoviral overexpression of ABCB8, or (F) in ABCB8 TG and NTG mice treated with DOX. (G) Mitochondrial iron and (H) cytosolic iron levels in heart samples from patients without cardiomyopathy (control), patients with cardiomyopathy from non–DOX-related causes (CM), or patients with DOX-induced cardiomyopathy (DOX CM) (n = 5). Data are presented as mean ± SEM. *P < 0.05.