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*

*Corresponding author for this work

Research output: Contribution to journalArticle

315 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)617-630
Number of pages14
JournalJournal of Clinical Investigation
Volume124
Issue number2
DOIs
StatePublished - Feb 3 2014

ASJC Scopus subject areas

  • Medicine(all)

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    Ichikawa, Y., Ghanefar, M., Bayeva, M., Wu, R., Khechaduri, A., Naga Prasad, S. V., Mutharasan, R. K., Jairaj Naik, T., & Ardehali, H. (2014). Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. Journal of Clinical Investigation, 124(2), 617-630. https://doi.org/10.1172/JCI72931