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

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Article numbere62174
Pages (from-to)1-23
Number of pages23
JournaleLife
Volume10
DOIs
Accepted/In press8 Jan 2021
Published2 Feb 2021

Bibliographical note

Funding Information: We thank Dr Erika Cadoni, Dr Saki Nakagawa, and Mr. Darran Hardy for their excellent technical assistance. We thank Dr George Chennell and Ms Chen Liang, the Wohl Cellular Imaging Centre at King?s College London, for help with spinning disk confocal microscopy. This work was supported by grants from the British Heart Foundation (CH/11/3/29051 and RG/16/15/32294), the Fondation Leducq (RA15CVD04), the European Research Council (692659), Japan Society for the Promotion of Science KAKENHI (18H02807), and Osaka University (International Joint Research Promotion Program) to K Otsu and from the British Heart Foundation to AM Shah (CH/1999001/11735 and RE/13/ 2/30182). Publisher Copyright: © Ito et al. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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  • eLife revised Main text 24122020

    eLife_revised_Main_text_24122020.pdf, 3.51 MB, application/pdf

    Uploaded date:08 Jan 2021

    Version:Accepted author manuscript

    Licence:CC BY

King's Authors

Abstract

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.

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