What happens when the transferrin receptor is mutated and cannot bind Fe³⁺ at acidic pH?
Iron uptake in proliferating cells depends on transferrin receptor mediated endocytosis tightly coupled to endosomal acidification. At extracellular pH 7.4 holo transferrin carrying two ferric ions binds transferrin receptor 1 homodimer with nanomolar affinity, clusters via AP2 clathrin adaptor and internalizes into early endosomes. Vacuolar ATPase acidifies lumen to about pH 5.5, protonation of transferrin histidines and nearby receptor residues induces conformational opening of transferrin lobes, reducing Fe3+ affinity by orders of magnitude and releasing ferric iron while apo transferrin remains bound to receptor due to retained high affinity at acidic pH. Liberated Fe3+ reduced to Fe2+ by ferrireductase STEAP3, exported through divalent metal transporter DMT1 into cytosolic labile iron pool for use in heme, Fe S clusters or storage in ferritin. Recycling vesicles return complex to plasma membrane where neutral pH dissociates apo transferrin for reuse. If receptor mutation prevents iron release at low pH, transferrin stays iron locked, endosomal iron export fails, cytosol becomes deficient, IRP IRE system upregulates receptor and represses ferritin, but iron does not accumulate in mitochondria nor cause rapid receptor degradation.
Ref: Alberts et al., Molecular Biology of the Cell, 7th ed., Chapter 13: Endocytosis and Transferrin Iron Transport.