Key result
CRISPR, Rho activation, or iron rescues endocytosis-driven subcellular iron deficiency in DCM cardiomyocytes.
Why the study?
Defective subcellular iron uptake mechanisms that are independent of systemic absorption are incompletely understood in heart failure.
Does correction of TPM1-L185F mutation, Rho activator II, or iron supplementation improve subcellular iron uptake and contractility in DCM iPSC-derived cardiomyocytes?
Does correction of TPM1-L185F mutation, Rho activator II, or iron supplementation improve subcellular iron uptake and contractility in DCM iPSC-derived cardiomyocytes?
Impaired clathrin-mediated endocytosis causes subcellular iron deficiency in DCM cardiomyocytes, which can be rescued by iron supplementation or targeted molecular therapies.
Should not yet change iron management in DCM; extends subcellular mechanisms but leaves open clinical translation.
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.
No takes yet. Share an insight, caveat, or question.
Dai et al. (2023) studied Dilated cardiomyopathy. CRISPR correction, Rho activator II, or iron supplementation vs. Untreated DCM models was evaluated on Subcellular iron uptake, endocytosis defects, and contractility. Impaired clathrin-mediated endocytosis causes subcellular iron deficiency in DCM cardiomyocytes, which can be rescued by CRISPR correction, Rho activator II, or iron supplementation.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: