An Alternative Mechanism of Subcellular Iron Uptake Deficiency in Cardiomyocytes


Dai Y, Ignatyeva N, Xu H, Wali R, Toischer K, Brandenburg S, Lenz C, Pronto J, Fakuade FE, Sossalla S, Zeisberg EM, Janshoff A, Kutschka I, Voigt N, Urlaub H, Rasmussen TB, Mogensen J, Lehnart SE, Hasenfuss G, Ebert A


Circulation Research


Circ Res. 2023 Jun 14.


Background: Systemic defects in intestinal iron absorption, circulation, and retention cause iron deficiency in 50% of patients with heart failure. Defective subcellular iron uptake mechanisms that are independent of systemic absorption are incompletely understood. The main intracellular route for iron uptake in cardiomyocytes is clathrin-mediated endocytosis.
Methods: We investigated subcellular iron uptake mechanisms in patient-derived and CRISPR/Cas–edited induced pluripotent stem cell–derived cardiomyocytes as well as patient-derived heart tissue. We used an integrated platform of MS-DIA–based proteomics and signaling pathway interrogation. We employed a genetic iPSC model of 2 inherited mutations (TnT [troponin T]-R141W and TPM1 [tropomyosin 1]-L185F) that lead to dilated cardiomyopathy (DCM), a frequent cause of heart failure, to study the underlying molecular dysfunctions of DCM mutations.
Results: We identified a druggable molecular pathomechanism of impaired subcellular iron deficiency that is independent of systemic iron metabolism. Clathrin-mediated endocytosis defects as well as impaired endosome distribution and cargo transfer were identified as a basis for subcellular iron deficiency in DCM-induced pluripotent stem cell–derived cardiomyocytes. The clathrin-mediated endocytosis defects were also confirmed in the hearts of patients with DCM with end-stage heart failure. Correction of the TPM1-L185F mutation in DCM patient–derived induced pluripotent stem cells, treatment with a small compound, RhoA activator II, or iron supplementation rescued the molecular disease pathway and recovered contractility. Phenocopying the effects of the TPM1-L185F mutation into WT induced pluripotent stem cell–derived cardiomyocytes could be ameliorated by iron supplementation.
Conclusions: Our findings suggest that impaired endocytosis and cargo transport resulting in subcellular iron deficiency could be a relevant pathomechanism for patients with DCM carrying inherited mutations. Insight into this molecular mechanism may contribute to the development of treatment strategies and risk management in heart failure.


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