Iron derived from autophagy-mediated ferritin degradation induces cardiomyocyte death and heart failure in mice

eLife

Ajay M Shah¹  Shigemiki Omiya²  Tomokazu Murakawa³  Manabu Taneike⁴  Yohei Tanada⁵  Kazuhiko Nishida⁵  Mara-Camelia Rusu⁵  Hiromichi Ueda⁵  Hajime Abe⁵  Kazuki Nakahara⁵  Michio Asahi⁵  Jumpei Ito⁵  Kinya Otsu⁵ 

[1] Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan;Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka, Japan;Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan;Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka, Japan;The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom;

关键词: autophagy;    iron;    necrosis;    ferritin;    heart failure;   

DOI  :  10.7554/eLife.62174

来源: DOAJ

【 摘 要 】

Heart failure is a major public health problem, and abnormal iron metabolism is common in patients with heart failure. Although iron is necessary for metabolic homeostasis, it induces a programmed necrosis. Iron release from ferritin storage is through nuclear receptor coactivator 4 (NCOA4)-mediated autophagic degradation, known as ferritinophagy. However, the role of ferritinophagy in the stressed heart remains unclear. Deletion of Ncoa4 in mouse hearts reduced left ventricular chamber size and improved cardiac function along with the attenuation of the upregulation of ferritinophagy-mediated ferritin degradation 4 weeks after pressure overload. Free ferrous iron overload and increased lipid peroxidation were suppressed in NCOA4-deficient hearts. A potent inhibitor of lipid peroxidation, ferrostatin-1, significantly mitigated the development of pressure overload-induced dilated cardiomyopathy in wild-type mice. Thus, the activation of ferritinophagy results in the development of heart failure, whereas inhibition of this process protects the heart against hemodynamic stress.

【 授权许可】

Unknown