Iron control of erythroid development by a novel aconitase-associated regulatory pathway.
Human red cell differentiation requires the action of erythropoietin on committed progenitor cells. In iron deficiency, committed erythroid progenitors lose responsiveness to erythropoietin, resulting in hypoplastic anemia. To address the basis for iron regulation of erythropoiesis, we established primary hematopoietic cultures with transferrin saturation levels that restricted erythropoiesis but permitted granulopoiesis and megakaryopoiesis. Experiments in this system identified as a critical regulatory element the aconitases, multifunctional iron-sulfur cluster proteins that metabolize citrate to isocitrate. Iron restriction suppressed mitochondrial and cytosolic aconitase activity in erythroid but not granulocytic or megakaryocytic progenitors. An active site aconitase inhibitor, fluorocitrate, blocked erythroid differentiation in a manner similar to iron deprivation. Exogenous isocitrate abrogated the erythroid iron restriction response in vitro and reversed anemia progression in iron-deprived mice. The mechanism for aconitase regulation of erythropoiesis most probably involves both production of metabolic intermediates and modulation of erythropoietin signaling. One relevant signaling pathway appeared to involve protein kinase Calpha/beta, or possibly protein kinase Cdelta, whose activities were regulated by iron, isocitrate, and erythropoietin.
Bullock
Grant C
GC
Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Delehanty
Lorrie L
LL
Talbot
Anne-Laure
AL
Gonias
Sara L
SL
Tong
Wing-Hang
WH
Rouault
Tracey A
TA
Dewar
Brian
B
Macdonald
Jeffrey M
JM
Chruma
Jason J
JJ
Goldfarb
Adam N
AN
D018798:Anemia, Iron-Deficiency / Q000097:blood / Q000209:etiology / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007501:Iron / Q000494:pharmacology*; D000090463:Iron Deficiencies; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism*; D007523:Isocitrates / Q000008:administration & dosage; D020014:K562 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects
D007523:Isocitrates; C034219:isocitric acid; D007501:Iron; D035941:Iron Regulatory Protein 1
Blood. 2007 Jan 15;109(2):811-8
17003376
Science. 2004 Jul 9;305(5681):242-5
15247478
Blood. 1994 Dec 1;84(11):3915-24
7949148
IUBMB Life. 2000 May;49(5):457-66
10902579
Cell. 2004 Apr 30;117(3):285-97
15109490
EMBO J. 2004 Jan 28;23(2):386-95
14726953
Blood. 2008 Jun 1;111(11):5390-9
18349318
Nature. 2002 Jan 10;415(6868):180-3
11805837
Cell. 2004 Nov 12;119(4):529-42
15537542
Biochem J. 2000 Oct 1;351(Pt 1):95-105
10998351
FEBS Lett. 1996 Aug 26;392(2):77-80
8772178
J Nutr. 2003 May;133(5 Suppl 1):1510S-6S
12730455
Blood. 2007 Sep 15;110(6):2182-9
17540841
Nature. 2008 Jan 17;451(7176):335-9
18202658
Science. 2004 Dec 17;306(5704):2087-90
15604406
EMBO J. 2001 Dec 3;20(23):6909-18
11726526
J Neurochem. 1987 May;48(5):1377-85
3559554
J Appl Toxicol. 2006 Mar-Apr;26(2):148-61
16252258
J Biol Chem. 1998 Feb 27;273(9):5279-87
9478985
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13699-703
8942997
Blood. 2009 Jun 18;113(25):6440-8
19380871
Mol Cell Biol. 2007 May;27(9):3282-9
17325041
Blood. 2007 Jul 15;110(2):752-61
17429006
Blood. 1999 Feb 15;93(4):1178-88
9949160
Ann Clin Lab Sci. 2007 Summer;37(3):288-90
17709697
Semin Hematol. 2005 Oct;42(4):206-20
16210034
Blood. 2000 Aug 1;96(3):823-33
10910892
Nature. 2006 Mar 2;440(7080):96-100
16511496
J Nutr. 1998 Mar;128(3):525-35
9482759
Blood. 2004 May 1;103(9):3326-35
14715640
Biochimie. 2006 Feb;88(2):163-9
16139409
N Engl J Med. 2005 Mar 10;352(10):1011-23
15758012
Dev Cell. 2005 Nov;9(5):617-28
16256737
Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):10907-12
15263083
Blood. 2006 Jan 15;107(2):508-13
16166586
Blood. 2003 May 1;101(9):3690-8
12393473
Am J Hematol. 1992 Nov;41(3):147-50
1415188
J Org Chem. 1996 Mar 8;61(5):1817-1821
11667054
Annu Rev Nutr. 2004;24:105-31
15189115
Cell Mol Life Sci. 2009 Mar;66(5):919-32
19153662
J Cell Physiol. 1986 Feb;126(2):298-306
3944211
Cell Metab. 2006 Mar;3(3):199-210
16517407
J Nutr. 2002 Apr;132(4):643-51
11925455
Cancer Res. 2006 Mar 15;66(6):2990-6
16540647
Blood. 2006 May 15;107(10):4142-8
16434484
Mol Cell Biol. 2004 Sep;24(17):7779-94
15314183