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Iron control of erythroid microtubule cytoskeleton as a potential target in treatment of iron-restricted anemia.

ABSTRACT: 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.

SUBMITTER: Goldfarb AN

PROVIDER: S-EPMC7955080 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Iron control of erythroid microtubule cytoskeleton as a potential target in treatment of iron-restricted anemia.

Goldfarb Adam N AN Freeman Katie C KC Sahu Ranjit K RK Elagib Kamaleldin E KE Holy Maja M Arneja Abhinav A Polanowska-Grabowska Renata R Gru Alejandro A AA White Zollie Z Khalil Shadi S Kerins Michael J MJ Ooi Aikseng A Leitinger Norbert N Luckey Chance John CJ Delehanty Lorrie L LL

Nature communications 20210312 1

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 ...[more]

PMID: 33712594

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Project description:Preoperative anemia occurs in about one third of patients who undergo elective surgery and is associated with an impaired outcome. Therefore, screening of preoperative anemia was established in the context of a multidisciplinary Patient Blood Management (PBM) program at the University Hospital of Muenster, Germany. Anemic patients without contraindications were treated with intravenous (IV) iron (ferric carboxymaltose) to increase their hemoglobin (Hgb) levels and hence to treat anemia prior to surgery. Interestingly, we detected a large variability in the response of Hgb levels after IV iron administration. Systemic iron homeostasis is mainly regulated by the hepatic hormone hepcidin, which regulates the cell surface expression of the sole known iron exporter ferroportin. The objective of this retrospective pilot study was to analyze the potential of hepcidin to predict the response of anemic patients to preoperative IV iron treatment measured as increase in Hgb. Serum samples of non-anemic (n = 48), untreated anemic (n = 64) and anemic patients treated with IV iron (n = 79), in total 191 patients, were collected between October 2014 until June 2016. Serum hepcidin levels were determined and data were analyzed retrospectively. The analysis revealed at first a correlation between serum hepcidin levels and the parameters of the iron status. Second, patients treated with IV iron showed a noticeably higher increase in their delta Hgb level between PBM consultation and surgery (0.45g/dl [0.05, 1.05] compared to patients without IV iron (0.1g/dl [-0.48, 0.73], *p = 0.03). Patients were then grouped into 'non-responders', defined as delta Hgb <0.6g/dl and 'responders', with delta Hgb ≥0.6g/dl between the day of IV iron treatment and the day of surgery. Within normal ranges and clinically unapparent, a statistically noticeable difference between responders and non-responders was found for CRP and leukocytes. Serum hepcidin levels were higher in the group of non-responders (10.6ng/ml [3.93, 34.77]) compared to responders (2.1ng/ml [0.25, 7.97], *p = 0.04). To conclude, the data of this retrospective pilot study indicate that hepcidin might be a promising biomarker to predict a patient`s responsiveness to IV iron in preoperative anemia treatment. Prospective studies have to investigate serum hepcidin levels as a biomarker to guide physician`s decision on IV iron substitution.

Dataset Information

Iron control of erythroid microtubule cytoskeleton as a potential target in treatment of iron-restricted anemia.

Publications

Iron control of erythroid microtubule cytoskeleton as a potential target in treatment of iron-restricted anemia.

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