Non-transferrin-bound iron (NTBI) uptake by T lymphocytes: evidence for the selective acquisition of oligomeric ferric citrate species

Joao Arezes; Monica Costa; Ines Vieira; Vera Dias; Xiao L Kong; Rui Fernandes; Matthijn Vos; Anna Carlsson; Yuri Rikers; Graça Porto; Maria Rangel; Robert C Hider; Jorge P Pinto

doi:10.1371/journal.pone.0079870

Non-transferrin-bound iron (NTBI) uptake by T lymphocytes: evidence for the selective acquisition of oligomeric ferric citrate species

PLoS One. 2013 Nov 21;8(11):e79870. doi: 10.1371/journal.pone.0079870. eCollection 2013.

Authors

Joao Arezes¹, Monica Costa, Ines Vieira, Vera Dias, Xiao L Kong, Rui Fernandes, Matthijn Vos, Anna Carlsson, Yuri Rikers, Graça Porto, Maria Rangel, Robert C Hider, Jorge P Pinto

Affiliation

¹ Basic and Clinical Research on Iron Biology, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.

Abstract

Iron is an essential nutrient in several biological processes such as oxygen transport, DNA replication and erythropoiesis. Plasma iron normally circulates bound to transferrin. In iron overload disorders, however, iron concentrations exceed transferrin binding capacity and iron appears complexed with low molecular weight molecules, known as non-transferrin-bound iron (NTBI). NTBI is responsible for the toxicity associated with iron-overload pathologies but the mechanisms leading to NTBI uptake are not fully understood. Here we show for the first time that T lymphocytes are able to take up and accumulate NTBI in a manner that resembles that of hepatocytes. Moreover, we show that both hepatocytes and T lymphocytes take up the oligomeric Fe3Cit3 preferentially to other iron-citrate species, suggesting the existence of a selective NTBI carrier. These results provide a tool for the identification of the still elusive ferric-citrate cellular carrier and may also open a new pathway towards the design of more efficient iron chelators for the treatment of iron overload disorders.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD4-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / metabolism
Cells, Cultured
Endocytosis / physiology
Ferric Compounds / metabolism*
Hep G2 Cells
Hepatocytes / metabolism
Humans
Iron / metabolism*
Kinetics
T-Lymphocytes / metabolism*

Substances

Ferric Compounds
ferric citrate
Iron

Grants and funding

This work is funded by FEDER funds through the Operational Competitiveness Programme – COMPETE, by national funds through FCT – Fundação para a Ciência e a Tecnologia under the projects FCOMP-01-0124-FEDER-015823(PTDC/SAU-MET/113011/2009), FCOMP-01-0124-FEDER-007046(PTDC/BIA-BCM/66818/2006) FCOMP-01-0124-FEDER-007506(PTDC/SAU-GMG/67868/2006) and by the INOVA Foundation. JA, IV, MC and VD are recipients of FCT fellowships (www.fct.pt). JPP is supported by Programa Ciência (sponsored by POPH-QREN (4.2), with match-funding from the European Social Fund and Portuguese funds from the MCTES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.