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

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.

Newcastle-disease-virus-induced ferroptosis through nutrient deprivation and ferritinophagy in tumor cells

“…of autophagy that contributes to the initiation of ferroptosis through the degradation of ferritin by lysosomes (Qin et al, 2021;Zhou et al, 2020). Nuclear receptor coactivator 4 (NCOA4), a selective cargo receptor, promotes ferritin degradation during ferritinophagy (Goodall and Thorburn, 2014;Ito et al, 2021;Nai et al, 2021). The accumulation of ferrous iron triggers ROS generation through the Fenton reaction, and ferritinophagy modulates ferroptosis by increasing the levels of lipid peroxidation (Ajoolabady et al, 2021).…”

Formaldehyde induces ferritinophagy to damage hippocampal neuronal cells

“…Because that NCOA4 is necessary for the implementation of ferritinophagy, ferritinophagy can be hindered by deleting or inhibiting NCOA4 (Hou et al, 2016;Ito et al, 2021). For more persuasiveness that NCOA4-dependent ferritinophagy is the mechanism of FA-induced neurotoxicity, we purposefully silenced NCOA4 in HT22 cells before FA treatment through shRNA interference technology to investigate whether inhibiting NCOA4-dependent ferritinophagy reverses toxic damage resulting from FA.…”

Safety and efficacy of iron supplementation after myocardial infarction in mice with moderate blood loss anaemia

“…In iron therapies intended to improve AMI, the dose and time point of administration must be taken into the consideration, as higher iron concentrations generate oxidative stress and activate programmed apoptosis. 26 , 27 Additionally, lower concentrations of iron promote cell survival through increased inducible nitric oxide synthase activity and increased nitric oxide production. 28 , 29 In this study, we applied a dose of i.v.…”

“…Several studies demonstrated that the time point of iron treatment during AMI appears harmful in the acute phase of AMI, in particular during reperfusion, which is caused by mitochondrial iron accumulation and leads to impaired cardiac contractility due to increased ROS within the cardiomyocytes. 33 Besides, these toxic effects of early iron application during or prior to reperfusion were prevented by the administration of iron chelator DFO 15 min prior to and 15 min throughout of coronary occlusion of reperfusion, which showed a cardioprotective effect through improved myocardial high‐energy phosphate metabolism and LV contractility after a period of global ischaemia. 13 These data support that iron catalysis is involved in the production of oxygen‐derived free radicals during I/R injury.…”

“… 1 , 12 Anaemia is associated with post‐procedural complications with adverse in‐hospital outcomes and mortality after pPCI. 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 In addition, 30% of the patients with acute myocardial infarction (AMI) present with decreased baseline haemoglobin (Hb) concentrations, 6 which is correlated to a 15% to 25% risk of developing congestive heart failure (HF) during and after the event. 34 , 35 , 36 Anaemia itself is associated with reduced iron content in blood and thus iron deficiency (ID).…”