Mitoferrin is essential for erythroid iron assimilation

Abstract

Iron has a fundamental role in many metabolic processes, including electron transport, deoxyribonucleotide synthesis, oxygen transport and many essential redox reactions involving haemoproteins and Fe-S cluster proteins. Defective iron homeostasis results in either iron deficiency or iron overload. Precise regulation of iron transport in mitochondria is essential for haem biosynthesis, haemoglobin production and Fe-S cluster protein assembly during red cell development. Here we describe a zebrafish mutant, frascati (frs), that shows profound hypochromic anaemia and erythroid maturation arrest owing to defects in mitochondrial iron uptake. Through positional cloning, we show that the gene mutated in the frs mutant is a member of the vertebrate mitochondrial solute carrier family (SLC25) that we call mitoferrin (mfrn). mfrn is highly expressed in fetal and adult haematopoietic tissues of zebrafish and mouse. Erythroblasts generated from murine embryonic stem cells null for Mfrn (also known as Slc25a37) show maturation arrest with severely impaired incorporation of 55Fe into haem. Disruption of the yeast mfrn orthologues, MRS3 and MRS4, causes defects in iron metabolism and mitochondrial Fe-S cluster biogenesis. Murine Mfrn rescues the defects in frs zebrafish, and zebrafish mfrn complements the yeast mutant, indicating that the function of the gene may be highly conserved. Our data show that mfrn functions as the principal mitochondrial iron importer essential for haem biosynthesis in vertebrate erythroblasts.

The role of lysosomes in iron metabolism and recycling

“…However, the details of how iron is targeted to these organelles or how heme is exported to the cytosol remain unclear. The recently detected proteins mitoferrin 1 and mitoferrin 2 might act as iron-transporters over the inner mitochondrial membranes (Paradkar et al, 2009, Shaw et al, 2006, although they cannot be the only transporters involved because their deletion is not lethal. Since mitochondria are the main cellular producers of superoxide and hydrogen peroxide, one has to anticipate that mitochondrial iron is predominantly kept in a non-redox-active form since otherwise fulminant production of hydroxyl radicals would result.…”

Association between Mitochondrial Bioenergetics and Radiation- Related Fatigue: A Possible Mechanism and Novel Target

“…SLC25A37 provides a critical role of iron-consuming processes including heme synthesis and Fe-S cluster synthesis in mitochondria [45,49]. Over expression of SLC25A37 and increased mitoferron-1 protein lead to increased iron uptake into mitochondria and promotes heme synthesis [45], and this increased matrix free iron potentially can increase hydroxyl radical formation from hydrogen peroxide [46].…”

Regulation of heme biosynthesis and transport in metazoa

“…Next, iron is imported into the mitochondria by mitoferrins [33]. Mitoferrin 1 is highly expressed in vertebrate hematopoietic tissues and plays a primary role in supplying iron for heme synthesis in erythroid cells [33]. Its ubiquitously expressed paralog, mitoferrin 2, may be responsible for mitochondrial iron import in non-erythroid cells [34].…”

“…The specific chaperone that mediates iron transport from endosomes to the mitochondria has yet to be identified. Next, iron is imported into the mitochondria by mitoferrins [33]. Mitoferrin 1 is highly expressed in vertebrate hematopoietic tissues and plays a primary role in supplying iron for heme synthesis in erythroid cells [33].…”