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An Alternative Mechanism of Subcellular Iron Uptake Deficiency in Cardiomyocytes
Yuanyuan Dai1,2, Nadezda Ignatyeva1,2, Hang Xu1,2
1Heart Research Center Goettingen, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., S.S., E.M.Z., S.E.L., G.H., A.E.).
Insights
Heart failure patients often have iron deficiency due to impaired cellular iron uptake. This study reveals defective endocytosis in heart cells, offering new therapeutic targets for iron deficiency in heart failure.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Systemic iron deficiency affects 50% of heart failure patients.
- Subcellular iron uptake defects, independent of systemic absorption, are not fully understood.
- Clathrin-mediated endocytosis is the primary intracellular iron uptake route in cardiomyocytes.
Purpose of the Study:
- To investigate subcellular iron uptake mechanisms in heart failure.
- To explore molecular dysfunctions in dilated cardiomyopathy (DCM) using induced pluripotent stem cells (iPSCs).
- To identify druggable pathways for treating iron deficiency in heart failure.
Main Methods:
- Utilized patient-derived and CRISPR/Cas-edited iPSC-derived cardiomyocytes.
- Employed mass spectrometry-based proteomics and signaling pathway analysis.
- Studied genetic iPSC models of inherited DCM mutations (TnT-R141W, TPM1-L185F).
Main Results:
- Identified impaired clathrin-mediated endocytosis and endosome transport as a cause of subcellular iron deficiency.
- Confirmed endocytosis defects in iPSC-derived cardiomyocytes and patient heart tissue with DCM.
- Demonstrated that correcting mutations or supplementing iron/Rho activator II rescued the disease pathway and improved contractility.
Conclusions:
- Impaired endocytosis and cargo transport leading to subcellular iron deficiency is a key mechanism in inherited DCM.
- These findings offer potential therapeutic strategies for heart failure patients with inherited mutations.
- Understanding these molecular mechanisms can aid in developing new treatments and risk management approaches.
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 DIA-MA (mass spectrometry data-independent acquisition)-based proteomics and signaling pathway interrogation. We employed a genetic induced pluripotent stem cell 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 peptide, Rho 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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