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.

Red Blood Cell Morphologic Abnormalities in Patients Hospitalized for COVID-19

“…Of note, recent studies have also demonstrated that ferritin, which is typically elevated and prognostically relevant in severe COVID-19 ( Girelli et al, 2021 ), may be implicated. In particular, the heavy chain (FTH1) has been proposed to modulate cytoskeleton integrity in erythroid precursors, favoring microtubules disruption in iron restriction conditions ( Goldfarb et al, 2021 ).…”

Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins

“…Integration of iron status with erythroid development (Bullock et al, 2010;Richardson et al, 2013;Goldfarb et al, Regulates FECH activity (?) (Shah et al, 2012;Nakamura et al, 2013) CLPP ALAS turnover (Kubota et al, 2016;Rondelli et al, 2021) CLPX ALAS turnover, PPOX and FECH regulation; ALAS activation in yeast (Peoc'h et al, 2019;Phillips et al, 2019;Yien et al, 2017;Ducamp et al, 2021;Kubota et al, 2016;Rondelli et al, 2021;Kardon et al, 2015;Brown et al, 2018;Kardon et al, 2020) FLVCR1b Mitochondrial heme exporter (Quigley et al, 2004;Keel et al, 2008;Chiabrando et al, 2012;Doty et al, Mitochondrial iron import (Shaw et al, 2006;Christenson et al, 2018)…”

“…In erythroid cells, it integrates iron sufficiency with downstream enzymes in the heme synthesis pathway, ATP production and EPO-dependent PKC signaling to erythroid developmental pathways. Mitochondrial aconitase signaling may therefore be a mechanism by which mitochondrial iron status integrates with erythropoiesis; this is underscored by the ability of isocitrate to bypass erythroid iron restriction to restore terminal erythropoeisis ( Bullock et al, 2010 ; Richardson et al, 2013 ; Goldfarb et al, 2021 ).…”

DefectiveSlc7a7transport reduces erythropoietin compromising erythropoiesis and iron homeostasis

“…RBC maturation requires specific components to properly coordinate this process. Disruption in hemoglobin synthesis, which comprises one-third of the RBC protein content, leads to altered erythropoiesis (Kuhn et al, 2017;Liu et al, 2013) .Yet, hemoglobin is not the only key component as iron, erythropoietin (EPO), or ferritin are also well known to play essential roles in RBC generation (Beguin, 1998;Goldfarb et al, 2021;Moritz et al, 1997). In terms of metabolic requirements, Shima et al published the impact of arginine import on erythrocyte differentiation and proliferation throughout the cationic amino acid transporter 1 (CAT1), thereby indicating a crucial role not only of the iron-related components (hemoglobin, EPO, iron and ferritin) but also of metabolites such as arginine in the generation of mature RBCs (Shima et al, 2006).…”

“…RBC maturation requires specific components to properly coordinate this process. Disruption in hemoglobin synthesis, which comprises one-third of the RBC protein content, leads to altered erythropoiesis (Kuhn et al, 2017; Liu et al, 2013) .Yet, hemoglobin is not the only key component as iron, erythropoietin (EPO), or ferritin are also well known to play essential roles in RBC generation (Beguin, 1998; Goldfarb et al, 2021; Moritz et al, 1997). In terms of metabolic requirements, Shima et al .…”