TY - JOUR
T1 - Iron control of erythroid microtubule cytoskeleton as a potential target in treatment of iron-restricted anemia
AU - Goldfarb, Adam N.
AU - Freeman, Katie C.
AU - Sahu, Ranjit K.
AU - Elagib, Kamaleldin E.
AU - Holy, Maja
AU - Arneja, Abhinav
AU - Polanowska-Grabowska, Renata
AU - Gru, Alejandro A.
AU - White, Zollie
AU - Khalil, Shadi
AU - Kerins, Michael J.
AU - Ooi, Aikseng
AU - Leitinger, Norbert
AU - Luckey, Chance John
AU - Delehanty, Lorrie L.
N1 - Funding Information:
The authors thank Dr. Kyunghee Choi for providing KRN and G7 murine strains; Dr. Doris Haverstick for identifying and providing blood samples; Drs. Shalender Bhasin and Wen Guo for guidance with the KBA ACDI model; Dr. Stacey Criswell of the UVA Advanced Microscopy Facility for assistance with confocal immunofluorescence microscopy; Dr. Sanford Feldman of the UVA Center for Comparative Medicine for assistance with CBC analysis; Dr. Pat Pramoonjago of the UVA Biorepository and Tissue Research Facility for assistance with immunohistochemical staining of patient marrow samples; Joanne Lannigan and members of the UVA Flow Cytometry Core Facility; Julia Kao for thoughtful discussions; and Dr. Jeffrey M. Macdonald of the University of North Carolina Metabolomic Facility for NMR measurements of isocitrate and fumarate in cellular extracts. This research is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; R01 DK079924 and R01 DK101550), the National Heart, Lung, and Blood Institute (R01 HL149667), National Cancer Institute Center support (P30 CA44579), the Medical Scientist Training Program (5T32GM007267-38), and an NIDDK Research Supplement to Promote Diversity in Health-Related Research (3R01DK079924-09A1S1).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Anemias of chronic disease and inflammation (ACDI) result from restricted iron delivery to erythroid progenitors. The current studies reveal an organellar response in erythroid iron restriction consisting of disassembly of the microtubule cytoskeleton and associated Golgi disruption. Isocitrate supplementation, known to abrogate the erythroid iron restriction response, induces reassembly of microtubules and Golgi in iron deprived progenitors. Ferritin, based on proteomic profiles, regulation by iron and isocitrate, and putative interaction with microtubules, is assessed as a candidate mediator. Knockdown of ferritin heavy chain (FTH1) in iron replete progenitors induces microtubule collapse and erythropoietic blockade; conversely, enforced ferritin expression rescues erythroid differentiation under conditions of iron restriction. Fumarate, a known ferritin inducer, synergizes with isocitrate in reversing molecular and cellular defects of iron restriction and in oral remediation of murine anemia. These findings identify a cytoskeletal component of erythroid iron restriction and demonstrate potential for its therapeutic targeting in ACDI.
AB - Anemias of chronic disease and inflammation (ACDI) result from restricted iron delivery to erythroid progenitors. The current studies reveal an organellar response in erythroid iron restriction consisting of disassembly of the microtubule cytoskeleton and associated Golgi disruption. Isocitrate supplementation, known to abrogate the erythroid iron restriction response, induces reassembly of microtubules and Golgi in iron deprived progenitors. Ferritin, based on proteomic profiles, regulation by iron and isocitrate, and putative interaction with microtubules, is assessed as a candidate mediator. Knockdown of ferritin heavy chain (FTH1) in iron replete progenitors induces microtubule collapse and erythropoietic blockade; conversely, enforced ferritin expression rescues erythroid differentiation under conditions of iron restriction. Fumarate, a known ferritin inducer, synergizes with isocitrate in reversing molecular and cellular defects of iron restriction and in oral remediation of murine anemia. These findings identify a cytoskeletal component of erythroid iron restriction and demonstrate potential for its therapeutic targeting in ACDI.
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U2 - 10.1038/s41467-021-21938-2
DO - 10.1038/s41467-021-21938-2
M3 - Article
C2 - 33712594
AN - SCOPUS:85102494055
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1645
ER -