Astrocytes are central to iron and ascorbate homoeostasis within the brain. Although NTBI (non-transferrin-bound iron) may be a major form of iron imported by astrocytes in vivo, the mechanisms responsible remain unclear. The present study examines NTBI uptake by cultured astrocytes and the involvement of ascorbate and DMT1 (divalent metal transporter 1). We demonstrate that iron accumulation by ascorbate-deficient astrocytes is insensitive to both membrane-impermeant Fe(II) chelators and to the addition of the ferroxidase caeruloplasmin. However, when astrocytes are ascorbate-replete, as occurs in vivo, their rate of iron accumulation is doubled. The acquisition of this additional iron depends on effluxed ascorbate and can be blocked by the DMT1 inhibitor ferristatin/NSC306711. Furthermore, the calcein-accessible component of intracellular labile iron, which appears during iron uptake, appears to consist of only Fe(III) in ascorbate-deficient astrocytes, whereas that of ascorbate-replete astrocytes comprises both valencies. Our data suggest that an Fe(III)-uptake pathway predominates when astrocytes are ascorbate-deficient, but that in ascorbate-replete astrocytes, at least half of the accumulated iron is initially reduced by effluxed ascorbate and then imported by DMT1. These results suggest that ascorbate is intimately involved in iron accumulation by astrocytes, and is thus an important contributor to iron homoeostasis in the mammalian brain.
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Research Article|
October 25 2010
Two routes of iron accumulation in astrocytes: ascorbate-dependent ferrous iron uptake via the divalent metal transporter (DMT1) plus an independent route for ferric iron
Darius J.R. Lane;
Darius J.R. Lane
*Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Melbourne, VIC 3800, Australia
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Stephen R. Robinson;
Stephen R. Robinson
†Blood–Brain Interactions Group, School of Psychology and Psychiatry, Monash University, Melbourne, VIC 3800, Australia
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Hania Czerwinska;
Hania Czerwinska
†Blood–Brain Interactions Group, School of Psychology and Psychiatry, Monash University, Melbourne, VIC 3800, Australia
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Glenda M. Bishop;
Glenda M. Bishop
†Blood–Brain Interactions Group, School of Psychology and Psychiatry, Monash University, Melbourne, VIC 3800, Australia
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Alfons Lawen
Alfons Lawen
1
*Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Melbourne, VIC 3800, Australia
1To whom correspondence should be addressed (email alfons.lawen@monash.edu).
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Publisher: Portland Press Ltd
Received:
August 19 2010
Revision Received:
August 31 2010
Accepted:
September 06 2010
Accepted Manuscript online:
September 06 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 432 (1): 123–132.
Article history
Received:
August 19 2010
Revision Received:
August 31 2010
Accepted:
September 06 2010
Accepted Manuscript online:
September 06 2010
Citation
Darius J.R. Lane, Stephen R. Robinson, Hania Czerwinska, Glenda M. Bishop, Alfons Lawen; Two routes of iron accumulation in astrocytes: ascorbate-dependent ferrous iron uptake via the divalent metal transporter (DMT1) plus an independent route for ferric iron. Biochem J 15 November 2010; 432 (1): 123–132. doi: https://doi.org/10.1042/BJ20101317
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