An Alternative Mechanism of Subcellular Iron Uptake Deficiency in Cardiomyocytes

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.