Prion protein promotes kidney iron uptake via its ferrireductase activity

Swati Haldar, Ajai Tripathi, Juan Qian, Amber Beserra, Srinivas Suda, Matthew McElwee, Jerrold Turner, Ulrich Hopfer, Neena Singh

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Brain iron-dyshomeostasis is an important cause of neurotoxicity in prion disorders, a group of neurodegenerative conditions associated with the conversion of prion protein (PrPC) from its normal conformation to an aggregated, PrP-scrapie (PrPSc) isoform. Alteration of iron homeostasis is believed to result from impaired function of PrPNC in neuronal iron uptake via its ferrireductase activity. However, unequivocal evidence supporting the ferrireductase activity of PrPC is lacking. Kidney provides a relevant model for this evaluation because PrPC is expressed in the kidney, and ∼370 μg of iron are reabsorbed daily from the glomerular filtrate by kidney proximal tubule cells (PT), requiring ferrireductase activity. Here, we report that PrPC promotes the uptake of transferrin (Tf) and non-Tf-bound iron (NTBI) by the kidney in vivo and mainly NTBI by PT cells in vitro. Thus, uptake of 59Fe administered by gastric gavage, intravenously, or intraperitoneally was significantly lower in PrP-knock-out (PrP-/-) mouse kidney relative to PrP+/+ controls. Selective in vivo radiolabeling of plasma NTBI with 59Fe revealed similar results. Expression of exogenous PrPC in immortalized PT cells showed localization on the plasma membrane and intracellular vesicles and increased transepithelial transport of 59Fe-NTBI and to a smaller extent 59Fe-Tf from the apical to the basolateral domain. Notably, the ferrireductasedeficient mutant of PrP (PrPΔ51-89) lacked this activity. Furthermore, excess NTBI and hemin caused aggregation of PrPC to a detergent-insoluble form, limiting iron uptake. Together, these observations suggest that PrPC promotes retrieval of iron from the glomerular filtrate via its ferrireductase activity and modulates kidney iron metabolism.

Original languageEnglish (US)
Pages (from-to)5512-5522
Number of pages11
JournalJournal of Biological Chemistry
Volume290
Issue number9
DOIs
StatePublished - Feb 27 2015

Bibliographical note

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© 2015 by The American Society for Biochemistry and Molecular Biology Inc.

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