Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation
Yoshihiko Ichikawa, … , Tejaswitha Jairaj Naik, Hossein Ardehali
Yoshihiko Ichikawa, … , Tejaswitha Jairaj Naik, Hossein Ardehali
Published January 2, 2014
Citation Information: J Clin Invest. 2014;124(2):617-630. https://doi.org/10.1172/JCI72931.
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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 4

ABCB8 overexpression reduces DOX-induced mitochondrial iron accumulation and cardiotoxicity in vitro.

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ABCB8 overexpression reduces DOX-induced mitochondrial iron accumulation...
(A) Mitochondrial iron levels, as assessed by 55Fe in NRCMs transfected with adenoviruses coding for GFP or ABCB8 expression and treated with 10 μM DOX for 16 hours or vehicle control (n = 4). (B) RPA fluorescence in NRCMs transfected with the GFP or ABCB8 adenovirus and treated with 10 μM DOX for 16 hours. Lower levels of RPA fluorescence correspond to an increase in mitochondrial iron (n = 6). Scale bar: 100 μm. (C) ROS levels, as assessed by MitoSOX, in NRCMs transfected with the GFP or ABCB8 adenovirus and treated with DOX (10 μM for 16 hours) (n = 5). Scale bar: 100 μm. (D) Quantification of the ROS levels measured in C. (E) Cell viability, as assessed by MTS assay, in NRCMs transfected with the GFP or ABCB8 adenovirus and treated with 10 μM DOX for 16 hours (n = 6). (F) Mitochondrial DOX levels in NRCMs treated with control and ABCB8 siRNA, followed by treatment with 10 μM DOX for 16 hours (n = 4). (G) Mitochondrial DOX levels in NRCMs transfected with the GFP or ABCB8 adenovirus, followed by treatment with 10 μM DOX for 16 hours (n = 4). Data are presented as mean ± SEM. *P < 0.05.