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.
Highlights
Heart failure is the leading cause of death in developed countries (Ponikowski et al, 2016)
We found that nuclear receptor coactivator 4 (NCOA4)-dependent ferritinophagy is activated for degradation of ferritin in the heart in response to pressure overload and is detrimental in the stressed heart
We observed the reduction of FTH1 protein level in Ncoa4+/+ hearts 4 weeks after transverse aortic constriction (TAC) as we previously reported (Omiya et al, 2009)
Summary
Heart failure is the leading cause of death in developed countries (Ponikowski et al, 2016). While iron is essential for oxidative phosphorylation, metabolite synthesis, and oxygen transport (Andrews and Schmidt, 2007), it can generate toxic reactive hydroxyl radicals through the Fenton reaction (Papanikolaou and Pantopoulos, 2005). Iron-dependent necrotic cell death is characterized by iron overload and an increased level of lipid reactive oxygen species (ROS) such as lipid hydroperoxides, leading to phospholipid damage, plasma membrane disruption, and caspase- and necrosome-independent cell death (Dixon et al, 2012). The failure of GPX4 to clear lipid ROS leads to lipid peroxidation and ferroptosis (Yang et al, 2014). FTH1 has ferroxidase activity and sequestrates ferrous iron (Fe2 ) from the Fenton reaction in which the spontaneous oxidation to ferric iron (Fe3 ) donates single electrons to transform innocuous hydrogen peroxide to highly toxic hydroxyl free radicals. NCOA4-dependent iron release from ferritin storage is necessary for erythropoiesis (Bellelli et al, 2016)
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