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Oxidative stress induces mitochondrial iron overload and ferroptotic cell death.
Chen, Yi; Guo, Xiaoyun; Zeng, Yachang; Mo, Xiaoliang; Hong, Siqi; He, Hui; Li, Jing; Fatima, Sulail; Liu, Qinghang.
Afiliação
  • Chen Y; Department of Physiology and Biophysics, School of Medicine, University of Washington, 1705 NE Pacific Street, G424, Box 357290, Seattle, WA, 98195-7290, USA.
  • Guo X; Department of Physiology and Biophysics, School of Medicine, University of Washington, 1705 NE Pacific Street, G424, Box 357290, Seattle, WA, 98195-7290, USA.
  • Zeng Y; Department of Physiology and Biophysics, School of Medicine, University of Washington, 1705 NE Pacific Street, G424, Box 357290, Seattle, WA, 98195-7290, USA.
  • Mo X; Department of Physiology and Biophysics, School of Medicine, University of Washington, 1705 NE Pacific Street, G424, Box 357290, Seattle, WA, 98195-7290, USA.
  • Hong S; Department of Physiology and Biophysics, School of Medicine, University of Washington, 1705 NE Pacific Street, G424, Box 357290, Seattle, WA, 98195-7290, USA.
  • He H; Department of Physiology and Biophysics, School of Medicine, University of Washington, 1705 NE Pacific Street, G424, Box 357290, Seattle, WA, 98195-7290, USA.
  • Li J; Department of Physiology and Biophysics, School of Medicine, University of Washington, 1705 NE Pacific Street, G424, Box 357290, Seattle, WA, 98195-7290, USA.
  • Fatima S; Department of Physiology and Biophysics, School of Medicine, University of Washington, 1705 NE Pacific Street, G424, Box 357290, Seattle, WA, 98195-7290, USA.
  • Liu Q; Department of Physiology and Biophysics, School of Medicine, University of Washington, 1705 NE Pacific Street, G424, Box 357290, Seattle, WA, 98195-7290, USA. qcliu@uw.edu.
Sci Rep ; 13(1): 15515, 2023 09 19.
Article em En | MEDLINE | ID: mdl-37726294
ABSTRACT
Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (H2O2), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via heme degradation. Strikingly, oxidative stress also promoted HO-1 translocation to mitochondria, leading to mitochondrial iron overload and lipid reactive oxygen species (ROS) accumulation. Targeted inhibition of mitochondrial iron overload or ROS accumulation, by overexpressing mitochondrial ferritin (FTMT) or mitochondrial catalase (mCAT), respectively, markedly inhibited oxidative stress-induced ferroptosis. The levels of mitochondrial iron and lipid peroxides were also markedly increased in cardiomyocytes subjected to simulated ischemia and reperfusion (sI/R) or the chemotherapeutic agent doxorubicin (DOX). Overexpressing FTMT or mCAT effectively prevented cardiomyocyte death induced by sI/R or DOX. Taken together, oxidative stress induced by organic oxidants but not H2O2 primarily triggers ferroptotic cell death in cardiomyocyte through GPX4 and Bach1/HO-1 dependent mechanisms. Our results also reveal mitochondrial iron overload via HO-1 mitochondrial translocation as a key mechanism as well as a potential molecular target for oxidative stress-induced ferroptosis in cardiomyocytes.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Estresse Oxidativo / Sobrecarga de Ferro Limite: Humans Idioma: En Revista: Sci Rep Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Estresse Oxidativo / Sobrecarga de Ferro Limite: Humans Idioma: En Revista: Sci Rep Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos