An Alternative Mechanism of Subcellular Iron Uptake Deficiency in Cardiomyocytes

2023 | journal article. A publication with affiliation to the University of Göttingen.

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​An Alternative Mechanism of Subcellular Iron Uptake Deficiency in Cardiomyocytes​
Dai, Y.; Ignatyeva, N.; Xu, H.; Wali, R.; Toischer, K.; Brandenburg, S. & Lenz, C. et al.​ (2023) 
Circulation Research, art. CIRCRESAHA.122.321157​.​ DOI: 

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Dai, Yuanyuan; Ignatyeva, Nadezda; Xu, Hang; Wali, Ruheen; Toischer, Karl; Brandenburg, Sören; Lenz, Christof; Pronto, Julius; Fakuade, Funsho E.; Sossalla, Samuel; Ebert, Antje
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.
Issue Date
Circulation Research 
EXC 2067: Multiscale Bioimaging 
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion 
SFB 1002 | A12: Alternative molekulare Signaltransduktionswege durch Kardiomyopathie-verursachende Troponin-Mutationen 
SFB 1002 | A13: Bedeutung einer gestörten zytosolischen Calciumpufferung bei der atrialen Arrhythmogenese bei Patienten mit Herzinsuffizienz (HF) 
SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse 
SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente 
SFB 1190 | Z02: Massenspektrometrie-basierte Proteomanalyse 
Working Group
RG Hasenfuß (Transition zur Herzinsuffizienz) 
RG Janshoff 
RG Lehnart (Cellular Biophysics and Translational Cardiology Section) 
RG Toischer (Kardiales Remodeling) 
RG Urlaub (Bioanalytische Massenspektrometrie) 
RG Voigt (Molecular Pharmacology) 
RG E. Zeisberg (Kardiales Stroma) 
RG Brandenburg 
RG Ebert (Cardiovascular Cell Biology and Systems Medicine) 
RG Lenz 
RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung) 
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