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Updated: Jun 27, 2025

Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts
Published on: February 23, 2024
Structural basis for the intracellular regulation of ferritin degradation
Fabian Hoelzgen1,2, Thuy T P Nguyen3, Elina Klukin2
1The Kreitman School of Advanced Graduate Studies, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Abstract:
The interaction between nuclear receptor coactivator 4 (NCOA4) and the iron storage protein ferritin is a crucial component of cellular iron homeostasis. The binding of NCOA4 to the FTH1 subunits of ferritin initiates ferritinophagy-a ferritin-specific autophagic pathway leading to the release of the iron stored inside ferritin. The dysregulation of NCOA4 is associated with several diseases, including neurodegenerative disorders and cancer, highlighting the NCOA4-ferritin interface as a prime target for drug development. Here, we present the cryo-EM structure of the NCOA4-FTH1 interface, resolving 16 amino acids of NCOA4 that are crucial for the interaction. The characterization of mutants, designed to modulate the NCOA4-FTH1 interaction, is used to validate the significance of the different features of the binding site. Our results explain the role of the large solvent-exposed hydrophobic patch found on the surface of FTH1 and pave the way for the rational development of ferritinophagy modulators.
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