title: Expression and function of iron-regulatory proteins in retina.
abstract: Iron is essential for cell survival and function; yet excess iron is toxic to cells. Therefore, the cellular and whole-body levels of iron are regulated exquisitely. At least a dozen proteins participate in the regulation of iron homeostasis. Hemochromatosis, a genetic disorder of iron overload, is caused by mutations in at least five genes, namely HFE, hemojuvelin, Transferrin receptor 2, ferroportin, and hepcidin. Retina is separated from systemic circulation by inner and outer blood-retinal barriers; therefore it is widely believed that this tissue is immune to changes in systemic circulation. Even though hemochromatosis is associated with iron overload and dysfunction of a variety of systemic organs, little is known on the effects of this disease on the retina. Recent studies have shown that all five genes that are associated with hemochromatosis are expressed in the retina in a cell type-specific manner. The retinal pigment epithelium, which forms the outer blood-retinal barrier, expresses all of these five genes. It is therefore clearly evident that iron homeostasis in the retina is maintained locally by active participation of various iron-regulatory proteins. Excess iron is detrimental to the retina as evidenced from human studies and from mouse models of iron overload. Retinal iron homeostasis is disrupted in various clinical conditions such as hemochromatosis, aceruloplasminemia, age-related macular degeneration, and bacterial and viral infections.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA.
authors.forename: Jaya P
authors.initials: JP
authors.lastname: Gnana-Prakasam
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Martin
authors.forename: Sylvia B
authors.initials: SB
authors.lastname: Smith
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D001424:Bacterial Infections / Q000503:physiopathology; D001813:Blood-Retinal Barrier / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism; D058851:GPI-Linked Proteins; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D035925:Iron-Regulatory Proteins / Q000378:metabolism*; D008268:Macular Degeneration / Q000503:physiopathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D012160:Retina / Q000378:metabolism*; D012164:Retinal Diseases / Q000503:physiopathology; D014777:Virus Diseases / Q000503:physiopathology; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C103673:HFE protein, human; C481006:HJV protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D035925:Iron-Regulatory Proteins; D008565:Membrane Proteins; D000098742:Ferroportin; D005293:Ferritins
references.citation: Semin Liver Dis. 2005 Nov;25(4):450-60
references.pmid: 16315138
references.citation: J Mol Biol. 2009 Feb 27;386(3):717-32
references.pmid: 19150361
references.citation: Trends Microbiol. 2003 Apr;11(4):171-8
references.pmid: 12706995
references.citation: Blood. 2003 Apr 1;101(7):2858-64
references.pmid: 12456502
references.citation: Biochem J. 2009 Nov 11;424(2):243-52
references.pmid: 19715555
references.citation: Arch Ophthalmol. 2001 Oct;119(10):1417-36
references.pmid: 11594942
references.citation: Science. 2009 Aug 14;325(5942):877-80
references.pmid: 19679815
references.citation: Invest Ophthalmol Vis Sci. 2006 Oct;47(10):4238-44
references.pmid: 17003411
references.citation: Biochem J. 1984 Apr 1;219(1):1-14
references.pmid: 6326753
references.citation: Biochem J. 2009 May 1;419(3):533-43
references.pmid: 19191760
references.citation: Nature. 1997 Jul 31;388(6641):482-8
references.pmid: 9242408
references.citation: Hepatology. 2009 Dec;50(6):1992-2000
references.pmid: 19824072
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):570-5
references.pmid: 19126685
references.citation: J Biol Chem. 2008 Jun 20;283(25):17494-502
references.pmid: 18445598
references.citation: Semin Liver Dis. 2005 Nov;25(4):411-9
references.pmid: 16315135
references.citation: Biochem J. 2008 Apr 1;411(1):79-88
references.pmid: 18042040
references.citation: Mol Cell Biol. 2010 Feb;30(3):781-92
references.pmid: 19995918
references.citation: Nat Genet. 2009 Apr;41(4):482-7
references.pmid: 19252486
references.citation: J Hepatol. 2009 Feb;50(2):394-401
references.pmid: 19070914
references.citation: Biochem Biophys Res Commun. 2009 Jan 23;378(4):727-31
references.pmid: 19059216
references.citation: Invest Ophthalmol Vis Sci. 2000 Jul;41(8):2343-51
references.pmid: 10892882
references.citation: PLoS One. 2009 Aug 12;4(8):e6618
references.pmid: 19672300
references.citation: J Biol Chem. 1999 Jul 23;274(30):20826-32
references.pmid: 10409623
references.citation: MMWR Recomm Rep. 1998 Apr 3;47(RR-3):1-29
references.pmid: 9563847
references.citation: Free Radic Biol Med. 1997;23(1):26-33
references.pmid: 9165294
references.citation: Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2539-43
references.pmid: 7708681
references.citation: Hematol J. 2004;5(5):373-80
references.pmid: 15448662
references.citation: Gastroenterology. 2009 Oct;137(4):1489-97
references.pmid: 19591830
references.citation: Prog Retin Eye Res. 2007 Nov;26(6):649-73
references.pmid: 17921041
references.citation: Invest Ophthalmol Vis Sci. 2009 Apr;50(4):1895-902
references.pmid: 19151392
references.citation: Br J Ophthalmol. 1972 Apr;56(4):338-42
references.pmid: 5038719
references.citation: Blood. 2009 Jun 11;113(24):6225-36
references.pmid: 19380872
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10653-8
references.pmid: 12134060
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3800-5
references.pmid: 19234114
references.citation: Blood. 2008 May 15;111(10):5195-204
references.pmid: 18326817
references.citation: Invest Ophthalmol Vis Sci. 2008 Jun;49(6):2728-36
references.pmid: 18326691
references.citation: Ophthalmologica. 1998;212(1):11-4
references.pmid: 9438577
references.citation: Annu Rev Nutr. 2003;23:283-301
references.pmid: 12626689
references.citation: Blood. 2009 Sep 17;114(12):2515-20
references.pmid: 19622835
references.citation: J Biol Chem. 2009 Dec 11;284(50):34998-5014
references.pmid: 19840950
references.citation: Cell Metab. 2009 Mar;9(3):217-27
references.pmid: 19254567
references.citation: Biometals. 2009 Feb;22(1):77-87
references.pmid: 19130266
references.citation: Blood. 1995 Dec 1;86(11):4050-3
references.pmid: 7492760
references.citation: J Virol. 2003 Apr;77(8):4731-8
references.pmid: 12663780
references.citation: Annu Rev Med. 2006;57:331-47
references.pmid: 16409153
references.citation: Nat Genet. 2000 May;25(1):14-5
references.pmid: 10802645
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12413-8
references.pmid: 16116091
references.citation: Surv Ophthalmol. 2000 Sep-Oct;45(2):115-34
references.pmid: 11033038
references.citation: Hematology Am Soc Hematol Educ Program. 2006;:29-35, 507
references.pmid: 17124036
references.citation: Arch Ophthalmol. 2005 Dec;123(12):1745-6
references.pmid: 16344450
references.citation: Haematologica. 2009 Jun;94(6):765-72
references.pmid: 19454495
references.citation: Semin Ophthalmol. 2007 Oct-Dec;22(4):229-40
references.pmid: 18097986
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13850-5
references.pmid: 15365174
references.citation: Nat Genet. 1995 Dec;11(4):444-6
references.pmid: 7493028
references.citation: Dev Cell. 2009 Jan;16(1):35-46
references.pmid: 19154717
references.citation: Haematologica. 2009 Jun;94(6):840-9
references.pmid: 19377077
references.citation: Arch Ophthalmol. 1972 May;87(5):507-14
references.pmid: 5028091
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G590-4
references.pmid: 16537971
references.citation: Cell Metab. 2008 Feb;7(2):173-8
references.pmid: 18249176
references.citation: J Clin Invest. 1990 Dec;86(6):1991-8
references.pmid: 2123889
references.citation: J Biol Chem. 2009 Aug 21;284(34):22580-9
references.pmid: 19564337
references.citation: Mol Vis. 2004 Aug 26;10:598-607
references.pmid: 15354085
references.citation: Arch Ophthalmol. 2003 Aug;121(8):1099-105
references.pmid: 12912686
references.citation: J Mol Med (Berl). 2009 May;87(5):471-80
references.pmid: 19229506
references.citation: Surv Ophthalmol. 2003 May-Jun;48(3):257-93
references.pmid: 12745003
references.citation: Biochem Biophys Res Commun. 2009 Nov 20;389(3):399-404
references.pmid: 19716362