Reduced Ferritin heavy chain expression in cardiomyocytes induces ferroptosis-independent cardiac dysfunction in pressure-overloaded mouse hearts
S Omiya, K Nishinaka, J Ito, Y Kuramoto, K OtsuAbstract
Introduction
Although iron is necessary for metabolic homeostasis, excess iron may induce iron-dependent programmed necrosis, ferroptosis. Ferritin consists of heavy (FTH1) and light chains, and FTH1 converts Fe²⁺ to Fe³⁺ for safe sequestration, thereby regulating intracellular iron availability. Nuclear Receptor Coactivator 4 (NCOA4) interacts with FTH1 and mediates the autophagic delivery of ferritin to the autophagosome, a process known as ferritinophagy. We reported that excess iron derived from autophagy-mediated ferritin degradation induces cardiomyocyte death and heart failure in mice. Although the FTH1 protein level is steadily reduced in failing hearts, its biological significance remains unclear.
Methods
Cardiomyocyte-specific Fth1-deficient mice (FTH1-CKO) were generated and, at 10 weeks of age, underwent transverse aortic constriction (TAC) along with control mice (FTH1-WT) to induce cardiac pressure overload and heart failure. Four weeks later, body weight, blood pressure, and tissue weight were measured, and cardiac function was evaluated by echocardiography. Cardiac hypertrophy, fibrosis, cardiac remodeling markers, cardiomyocyte death, oxidative stress, blood and cardiac tissue iron content, and expression of iron-related proteins were also examined by histological, biochemical, and molecular biological analyses.
Results
Compared with the control group, TAC-operated FTH1-CKO showed similar body weight, blood pressure, and heart weight. Left ventricular fractional shortening, an index of cardiac function, in FTH1-CKO was significantly lower than FTH1-WT (FTH1-WT 40.0% vs. FTH1-CKO 33.8%). There were no significant differences in fibrosis and cardiac hypertrophy between the two groups, but Nppa mRNA levels, a marker of cardiac remodeling, were significantly increased in FTH1-CKO subjected to TAC than in FTH1-WT (FTH1-WT 5.9 vs. FTH1-CKO 13.8). Furthermore, malondialdehyde, an oxidative stress marker, and Ptgs2 mRNA levels, a ferroptosis marker, in the hearts were not significantly different between the two groups. Serum troponin I, an indicator of cardiomyocyte death, and serum iron levels were also not significantly different between the two groups. Iron levels in FTH1-CKO hearts were significantly increased compared with FTH1-WT hearts (FTH1-WT 32.3 μg/g wet tissues vs. FTH1-CKO 42.2 μg/g wet tissues), but the expression levels of iron-related proteins, except for FTH1, were not significantly different. These findings suggest that iron homeostasis in cardiomyocytes is disrupted by FTH1 deletion, resulting in insufficient iron utilization in cardiac tissues to maintain cardiac function.
Conclusions
Reduced FTH1 expression in cardiomyocytes disrupts cardiac iron homeostasis and contributes to cardiac dysfunction in chronic heart failure in a ferroptosis-independent manner.