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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 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.

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 9

Detailed analysis of cell death induced by DOX.

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Detailed analysis of cell death induced by DOX.
(A) Western blot of clea...
(A) Western blot of cleaved caspase substrate, cleaved caspase-3, and GPx4 in cultured cardiomyocytes, treated with DOX at 10, 20, and 30 hours after DOX treatment (n = 3). (B) Cell viability was assessed at 10, 20, and 30 hours after treatment with DOX, zVAD, and/or Fer-1 in cardiomyocytes (n = 6–12). (C) Details of cell death induced by DOX in cultured cardiomyocytes at each phase. Ferroptosis is defined as the percentage of cell death rescued by Fer-1 in DOX-induced cell death. Apoptosis is defined as the percentage of cell death rescued by zVAD in DOX-induced cell death. Others is defined as the percentage of cell death that was not rescued by a concomitant inhibition with Fer-1 and zVAD. Total percentage (100%) was divided into 3 categories (ferroptosis, apoptosis, and others) in accordance with their ratios. Detailed calculations are described in Supplemental Figure 9. 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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