Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF | Corrigendum
Research Article Cardiology

Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity

  • Text
  • PDF
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

×

Figure 5

Characterization of adenoviruses harboring cytosolic Gpx4 (Ad-cytoGPx4) and mitochondrial Gpx4 (Ad-mitoGPx4).

Options: View larger image (or click on image) Download as PowerPoint
Characterization of adenoviruses harboring cytosolic Gpx4 (Ad-cytoGPx4) ...
(A) GPx4 and GPx4-FLAG expression 48 hours after infection with adenoviruses harboring cytosolic and mitochondrial Gpx4 (0, 1, 3, 5, 10, and 20 MOI). (B) Western blot of GPx4, GPx4-FLAG, COX IV, and GAPDH in the cytosolic (C) and mitochondrial (M) fractions. (C) Immunofluorescence microscopy for localization of FLAG-tagged GPx4, MitoTracker Red, and DAPI in cultured cardiomyocytes. Scale bars: 10 μm. (D) Immunohistochemical electron microscopy of cultured cardiomyocytes 48 hours after infection with adenoviruses (3 MOI) harboring cytosolic (left panel) and mitochondrial Gpx4 (right). Single red arrowheads indicate gold particle. Scale bar: 200 nm. (n = 14 and 10, respectively). Data are shown as the mean ± SEM. Statistical significance was determined using 2-tailed Student’s t test. **P < 0.01.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts