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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 3

Heterodeletion of GPx4 aggravates DIC.

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Heterodeletion of GPx4 aggravates DIC.
(A) Western blot of GPx4 in heart...
(A) Western blot of GPx4 in heart tissue lysates from WT and GPx4 hetero-KO (hetKO) mice. (B) Echocardiographic images of WT and hetKO mice, treated with vehicle (Veh) and DOX, at day 14. (C) LVEF (n = 4–10). **P < 0.01 vs. WT/Veh. †P < 0.01, ††P < 0.01 vs. WT/DOX. Statistical significances at day 7 and 14 were determined using 1-way ANOVA with a post hoc Tukey’s HSD test. (D) Heart weight, normalized by tibial length (TL) at day 14 (n = 4–10). (E) Left ventricle (LV) weight, normalized by TL at day 14 (n = 4–10). (F) Western blot of acrolein and GPx4 in heart tissue lysates at day 14 (n = 6, each). (G) Malondialdehyde (MDA) in the myocardium at day 14 was measured by thiobarbituric acid reactive substances (TBARs) assay (n = 11–23). (H) Interstitial fibrosis in the LV evaluated using Masson trichrome staining in WT and hetKO mice treated with Veh or DOX. Scale bar: 50 μm (n = 4–10). Quantification of interstitial fibrosis, assessed by collagen volume fraction (%, interstitial fibrosis per total myocardium) (right panel). (I) TUNEL staining in WT and hetKO mice treated with Veh or DOX. Scale bar: 50 μm (n = 4–10). Arrowheads indicate TUNEL+ nuclei. Representative image of TUNEL+ cells at a high power (upper right panel). Scale bar: 10 μm (n = 4–10). 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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