Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity

JCI Insight. 2020 May 7;5(9):e132747. doi: 10.1172/jci.insight.132747.

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.

Keywords: Cardiology; Cardiovascular disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cardiomyopathies* / metabolism
  • Cardiomyopathies* / pathology
  • Cardiotoxicity
  • Cells, Cultured
  • Doxorubicin / toxicity*
  • Ferroptosis*
  • Lipid Peroxidation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria* / metabolism
  • Mitochondria* / pathology
  • Myocytes, Cardiac
  • Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism*
  • Rats, Sprague-Dawley
  • Ventricular Function, Left / drug effects

Substances

  • Doxorubicin
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • glutathione peroxidase 4, mouse
  • glutathione peroxidase 4, rat

Grants and funding

M.I.: 16H07049 and 18K15892, T.I.:17K09582, K.Y.: 17H03977 and 18K19405, H.T.:15H04815 and 19H03655