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Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity
Tomonori Tadokoro, … , Hirotaka Imai, Hiroyuki Tsutsui
Tomonori Tadokoro, … , Hirotaka Imai, Hiroyuki Tsutsui
Published May 7, 2020
Citation Information: JCI Insight. 2020;5(9):e132747. https://doi.org/10.1172/jci.insight.132747.
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Research Article Cardiology

Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity

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Abstract

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 Fe2+ reduction 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.

Authors

Tomonori Tadokoro, Masataka Ikeda, Tomomi Ide, Hiroko Deguchi, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Shouji Matsushima, Tomoko Koumura, Ken-ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui

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Figure 6

The roles of cytosolic and mitochondrial GPx4 in DOX-induced ferroptosis.

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The roles of cytosolic and mitochondrial GPx4 in DOX-induced ferroptosis...
(A) Western blot of GPx4, GPx4-FLAG, and cleaved caspase substrates in cardiomyocyte cell lysates, infected with Ad-cytoGPx4 and Ad-mitoGPx4 (n = 6). (B) Mitochondrial lipid peroxidation was measured using MitoPeDPP in the cultured cardiomyocyte, infected with Ad-cytoGPx4 and Ad-mitoGPx4 (n = 5). (C) Malondialdehyde (MDA) in the cultured cardiomyocyte, infected with Ad-cytoGPx4 and Ad-mitoGPx4, was measured using the thiobarbituric acid reactive substances (TBARs) assay (n = 3). (D) Cell viability was assessed 30 hours after treatment with DOX (2 μM; n = 5). Data are shown as the mean ± SEM. Statistical significance was determined using 1-way ANOVA with a post hoc Tukey’s HSD test. *P < 0.05, **P < 0.01.

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ISSN 2379-3708

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