Intracellular iron and heme trafficking and metabolism in developing erythroblasts

Abstract

Vertebrate red blood cells (RBCs) arise from erythroblasts in the human bone marrow through a process known as erythropoiesis. Iron uptake is a crucial hallmark, essential for heme biosynthesis in the differentiating erythroblasts, which are dedicated to producing hemoglobin. Erythropoiesis is facilitated by a network of intracellular transport proteins, chaperones, and circulating hormones. Intracellular iron is targeted to the mitochondria for incorporation into a porphyrin ring to form heme and cytosolic iron-sulfur proteins, including Iron Regulatory Protein 1 (IRP1). These processes are tightly regulated to prevent both excess and insufficient levels of iron and heme precursors. Crosstalk between the heme and iron-sulfur synthesizing pathways has been demonstrated to serve as a regulatory feedback mechanism. The activity of δ-aminolevulinic acid synthase (ALAS), the first and rate-limiting enzyme of heme biosynthesis, is a fundamental node of this regulation. Recently, the mitochondrial unfoldase, ClpX, has received attention as a novel key player that modulates this step in heme biogenesis, implicating a role in the pathophysiology of anemic diseases. This chapter reviews the canonical pathways in intracellular iron and heme trafficking and recent findings of iron and heme metabolism in vertebrate red cells. A discussion of the molecular approaches to studying iron and heme transport is provided to highlight opportunities for revealing therapeutic targets.

Mitochondrial dysfunction is signaled to the integrated stress response by OMA1, DELE1 and HRI

“…This finding raised the question of how dysfunction in the mitochondria is sensed by the cytosolic factor HRI. Since the canonical mechanism of HRI activation is a decrease of heme levels 20 and since key steps in heme biosynthesis occur in the mitochondria 21 , we hypothesized that heme depletion could be the signal by which HRI is activated upon mitochondrial dysfunction. We reasoned that if mitochondrial stress activated HRI through heme deprivation, hemin supplementation would block the oligomycin-induced ATF4 up-regulation.…”

The fungal mitochondrial membrane protein, BbOhmm, antagonistically controls hypoxia tolerance

“…Iron is an essential element involved in diverse biological processes, including oxygen transport, metabolism, respiration and cell cycle development (Zhang, 2014;Muckenthaler et al, 2017;Lv and Shang, 2018). A large portion of cellular iron is bound to heme that is used in a variety of proteins especially respiratory complexes, and cellular and mitochondrial iron concentrations are tightly regulated, including by various import/ export mechanisms (Napier et al, 2005;Kafina and Paw, 2017;Mon et al, 2019). Mitochondrial iron transporters, for example, DMT1 (MMT1), MRS3/4 and ABCB10 transport iron into mitochondria, whereas ABCB7 (Atm1) and ABCB8 (FXN), are mitochondrial iron efflux proteins (Mühlenhoff et al, 2003;Shaw et al, 2006;Chen et al, 2009;Zhao and Enns, 2012).…”

Dependence of heme biosynthesis on iron-sulfur cluster biogenesis: human ALAD is an unrecognized iron-sulfur protein

“…In mammalian cells, substantial amounts of iron are consumed by heme biosynthesis and iron-sulfur cluster (ISC) biogenesis 1,2 . Heme is synthesized by eight sequential enzymatic steps 3 , of which the rst takes place in the mitochondrial matrix, where 5-aminolevulinate synthase (ALAS) catalyzes the condensation of succinyl-CoA with glycine to generate ALA ( Figure S1) 3,4 .…”

“…Heme is synthesized by eight sequential enzymatic steps 3 , of which the rst takes place in the mitochondrial matrix, where 5-aminolevulinate synthase (ALAS) catalyzes the condensation of succinyl-CoA with glycine to generate ALA ( Figure S1) 3,4 . Two ALAS genes are present in vertebrates, a ubiquitously expressed ALAS1 and an erythroid-speci c ALAS2 2,5 . The mRNA of ALAS2 has an iron responsive element (IRE) in its 5'-untranslated region (UTR) and is post-transcriptionally regulated by the iron regulatory proteins (IRP1 and IRP2) 6,7 .…”