Iron Metabolism in the Disorders of Heme Biosynthesis

Abstract

Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At the same time, uncontrolled interactions between iron and its surrounding milieu may be damaging to cells and tissues. Heme-the iron-chelated form of protoporphyrin IX-is a macrocyclic tetrapyrrole and a coordination complex for diatomic gases, accurately engineered by evolution to exploit the catalytic, oxygen-binding, and oxidoreductive properties of iron while minimizing its damaging effects on tissues. The majority of the body production of heme is ultimately incorporated into hemoglobin within mature erythrocytes; thus, regulation of heme biosynthesis by iron is central in erythropoiesis. Additionally, heme is a cofactor in several metabolic pathways, which can be modulated by iron-dependent signals as well. Impairment in some steps of the pathway of heme biosynthesis is the main pathogenetic mechanism of two groups of diseases collectively known as porphyrias and congenital sideroblastic anemias. In porphyrias, according to the specific enzyme involved, heme precursors accumulate up to the enzyme stop in disease-specific patterns and organs. Therefore, different porphyrias manifest themselves under strikingly different clinical pictures. In congenital sideroblastic anemias, instead, an altered utilization of mitochondrial iron by erythroid precursors leads to mitochondrial iron overload and an accumulation of ring sideroblasts in the bone marrow. In line with the complexity of the processes involved, the role of iron in these conditions is then multifarious. This review aims to summarise the most important lines of evidence concerning the interplay between iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron in inherited conditions of altered heme biosynthesis.

Keywords: X-linked sideroblastic anemia; acute hepatic porphyrias; congenital hereditary porphyria; congenital sideroblastic anemias; erythropoiesis; erythropoietic protoporphyria; heme; iron; porphyria; porphyria cutanea tarda.

Figure 1

From iron to heme. Both iron metabolism and heme biosynthesis are complexly regulated to efficiently exploit the properties of iron in the most diverse biochemical settings. The mechanisms and factors depicted are described in detail in Section 2. ALAD, $\delta$-aminolaevulinate dehydratase; ALAS, $\delta$-aminolaevulinate-synthase; ABCB6, ATP-binding cassette super-family B member 6; ABCB7, ATP-binding cassette super-family B member 7; ABCB10, ATP-binding cassette super-family B member 10; ABCG2, ATP-binding cassette superfamily G member 2; BMP 6/2, bone morphogenetic protein 6 and 2 dimer; BMPRs, bone morphogenetic protein receptors; CLpX, caseinolytic mitochondrial matrix peptidase chaperone subunit X; CPOX, coproporphyrinogen III oxidase; DMT1, divalent metal transporter 1; ERFE, erythroferrone; FECH, ferrochelatase; FPN, ferroportin; FTX, frataxin; GLRX5, glutaredoxin 5; HAMP, hepcidin gene; HFE, human homeostatic iron regulator protein; HJV, hemojuvelin; HMBS, hydroxymethylbilane synthase; HSPA9, heat-shock protein family A member 9; IL-6, interleukin 6; IL-6R, interleukin 6 receptor; JAK, Janus kinase; LONP1, lon peptidase 1, mitochondrial; MICOS, mitochondrial contact site and cristae organizing system; MFRN1, mitoferrin 1; NCOA4, nuclear receptor coactivator 4; PLP, pyridoxal phosphate; PPOX, protoporphyrinogen oxidase; SLC25A38, mitochondrial solute carrier family member 25 A38 (glycine transporter); SMAD, small mother against decapentaplegic (protein family); STAT, signal transducer and activator of transcription protein; STEAP3, the six-transmembrane epithelial antigen of prostate 3 (metalloreductase); SUCLA, succinyl-CoA synthase; TF, transferrin; TFR1, transferrin receptor 1; TFR2, transferrin receptor 2; TMPRSS6, matriptase; UROD, uroporphyrinogen III decarboxylase; UROS, uroporphyrinogen III synthase. The red circles represent iron atoms; when needed, ferrous (²⁺) or ferric (³⁺) states are indicated. Created with Biorender.com (last accessed on 25 August 2022).