Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity

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

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicininduced 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.

Original languageEnglish
Article numbere132747
JournalJCI Insight
Volume5
Issue number9
DOIs
Publication statusPublished - May 7 2020

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Fingerprint Dive into the research topics of 'Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity'. Together they form a unique fingerprint.

Cite this