Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity

Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin-induced cardiomyopathy (DIC). This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. However, the molecular mechanism underlying this cardiotoxicity is yet...

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Bibliographic Details
Published in:JCI insight 2020-05, Vol.5 (9)
Main Authors: Tadokoro, Tomonori, Ikeda, Masataka, Ide, Tomomi, Deguchi, Hiroko, Ikeda, Soichiro, Okabe, Kosuke, Ishikita, Akihito, Matsushima, Shouji, Koumura, Tomoko, Yamada, Ken-Ichi, Imai, Hirotaka, Tsutsui, Hiroyuki
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Cardiomyopathies - metabolism
Cardiomyopathies - pathology
Cardiotoxicity
Cells, Cultured
Doxorubicin - toxicity
Ferroptosis
Lipid Peroxidation
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria - metabolism
Mitochondria - pathology
Myocytes, Cardiac
Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism
Rats, Sprague-Dawley
Ventricular Function, Left - drug effects
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Summary:Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin-induced cardiomyopathy (DIC). This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. However, the molecular mechanism underlying this cardiotoxicity is yet to be fully elucidated. Here, we show that DOX downregulated glutathione peroxidase 4 (GPx4) and induced excessive lipid peroxidation through DOX-Fe2+ complex in mitochondria, leading to mitochondria-dependent ferroptosis; we also show that mitochondria-dependent ferroptosis is a major cause of DOX cardiotoxicity. In DIC mice, the left ventricular ejection fraction was significantly impaired, and fibrosis and TUNEL+ cells were induced at day 14. Additionally, GPx4, an endogenous regulator of ferroptosis, was downregulated, accompanied by the accumulation of lipid peroxides, especially in mitochondria. These cardiac impairments were ameliorated in GPx4 Tg mice and exacerbated in GPx4 heterodeletion mice. In cultured cardiomyocytes, GPx4 overexpression or iron chelation targeting Fe2+ in mitochondria prevented DOX-induced ferroptosis, demonstrating that DOX triggered ferroptosis in mitochondria. Furthermore, concomitant inhibition of ferroptosis and apoptosis with ferrostatin-1 and zVAD-FMK fully prevented DOX-induced cardiomyocyte death. Our findings suggest that mitochondria-dependent ferroptosis plays a key role in progression of DIC and that ferroptosis is the major form of regulated cell death in DOX cardiotoxicity.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.132747