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

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

eLife (2021-02-03)
Jumpei Ito, Shigemiki Omiya, Mara-Camelia Rusu, Hiromichi Ueda, Tomokazu Murakawa, Yohei Tanada, Hajime Abe, Kazuki Nakahara, Michio Asahi, Manabu Taneike, Kazuhiko Nishida, Ajay M Shah, Kinya Otsu
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-NCOA4, (C-terminal) antibody produced in mouse, clone 1F11, purified immunoglobulin, buffered aqueous solution
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Anti-GPx4 Antibody, clone 1B4, clone 1B4, from rat
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Diethyl 3,4-pyrroledicarboxylate, 98%
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L-Glutamine–Penicillin–Streptomycin solution, L-glutamine 200 mM, streptomycin 10 mg/mL, penicillin 10,000 units, 0.1 μm filtered, BioReagent, suitable for cell culture
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Lectin from Triticum vulgaris (wheat), FITC conjugate, lyophilized powder
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Anti-GAPDH antibody, Mouse monoclonal, clone GAPDH-71.1, purified from hybridoma cell culture
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Isoprenaline hydrochloride
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Minimum Essential Medium Eagle, With Earle′s salts, non-essential amino acids and sodium bicarbonate, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
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1S,3R-RSL 3, ≥98% (HPLC)
Sigma-Aldrich
Ferrostatin-1, ≥95% (HPLC)