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

Adam N Goldfarb,Renata Polanowska-Grabowska,Shadi Khalil,Chance John Luckey,Michael J Kerins,Maja Holy,Aikseng Ooi,Ranjit K Sahu,Kamaleldin E Elagib,Lorrie L Delehanty,Alejandro A Gru,Abhinav Arneja,Norbert Leitinger,Zollie White,Katie C Freeman

doi:10.1038/s41467-021-21938-2

Adam N Goldfarb, Renata Polanowska-Grabowska + Show 13 more

Open Access

https://doi.org/10.1038/s41467-021-21938-2

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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.

Highlights

Anemias of chronic disease and inflammation (ACDI) result from restricted iron delivery to erythroid progenitors
We demonstrate a lineage-selective nutrient response pathway in which iron availability dictates cytoskeletal integrity through the action of ferritin on microtubules. This pathway is associated with the erythroid iron restriction response that underlies frequent clinical cases of anemia, such as anemias associated with chronic kidney disease
In an attempt to elucidate vesicular trafficking alterations previously described with erythroid iron restriction[13], we evaluated organelle morphology by immunofluorescence microscopy (IF)

Summary

Introduction

Anemias of chronic disease and inflammation (ACDI) result from restricted iron delivery to erythroid progenitors. 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. We demonstrate a lineage-selective nutrient response pathway in which iron availability dictates cytoskeletal integrity through the action of ferritin on microtubules This pathway is associated with the erythroid iron restriction response that underlies frequent clinical cases of anemia, such as anemias associated with chronic kidney disease. We further demonstrate feasibility of therapeutic targeting through the action of orally bioavailable metabolites on this pathway

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