Review
Cellular iron uptake, trafficking and metabolism: Key molecules and mechanisms and their roles in disease

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Highlights

  • Iron is a crucial transition metal for virtually all life.

  • Imported iron is stored or utilized with the cytoplasm or mitochondria.

  • Iron storage in ferritin involves iron chaperones (e.g., PCBPs).

  • Utilized iron is employed in anabolic pathways in cytoplasm/mitochondria.

  • Defects in iron trafficking lead to various human diseases.

Abstract

Iron is a crucial transition metal for virtually all life. Two major destinations of iron within mammalian cells are the cytosolic iron-storage protein, ferritin, and mitochondria. In mitochondria, iron is utilized in critical anabolic pathways, including: iron-storage in mitochondrial ferritin, heme synthesis, and iron–sulfur cluster (ISC) biogenesis. Although the pathways involved in ISC synthesis in the mitochondria and cytosol have begun to be characterized, many crucial details remain unknown. In this review, we discuss major aspects of the journey of iron from its initial cellular uptake, its modes of trafficking within cells, to an overview of its downstream utilization in the cytoplasm and within mitochondria. The understanding of mitochondrial iron processing and its communication with other organelles/subcellular locations, such as the cytosol, has been elucidated by the analysis of certain diseases e.g., Friedreich's ataxia. Increased knowledge of the molecules and their mechanisms of action in iron processing pathways (e.g., ISC biogenesis) will shape the investigation of iron metabolism in human health and disease.

Abbreviations

ABC
ATP-binding cassette
ALAS
δ-aminoleuvulinate synthase
CIA
cytosolic ISC protein assembly
DCYTB
duodenal cytochrome b
DMT1
divalent metal transporter 1
FBXL5
F-box and Leucine-rich Repeat Protein 5
FIH1
factor inhibiting HIF 1
FPN1
ferroportin 1
FTL
L-ferritin
FTH1
H-ferritin
HIF
hypoxia-inducible factor
FDXR
ferredoxin reductase
FDX1/2
ferredoxins 1 and 2
FRDA
Friedreich's ataxia
FTMT
mitochondrial-specific ferritin
GLRX5
glutaredoxin 5
IMM
inner mitochondrial membrane
IRP
iron regulatory protein
IRE
iron responsive element
ISC
iron–sulfur cluster
ISCU
ISC assembly enzyme
KH
K homology
LIP
labile iron pool
LYR
leucine–tyrosine–arginine
LYRM
LYR motif
LYRM4
LYR motif-containing 4
MFRN
mitoferrin
NCOA4
nuclear receptor coactivator 4
NFS1
NFS1 cysteine desulfurase
NTBI
non-transferrin-bound iron
OMM
outer mitochondrial membrane
PCBP
poly (rC)-binding protein
PHD
prolyl-4-hydroxylase domain-containing iron-dependent prolyl hydroxylase
PPIX
protoporphyrin IX
ROS
reactive oxygen species
SDHAF1
succinate dehydrogenase assembly factor 1
SDHB
succinate dehydrogenase subunit B
STEAP3
six trans-membrane epithelial antigen of the prostate 3
Tf
transferrin
TfR1
transferrin receptor 1
UTR
untranslated region
VDAC
voltage-dependent anion channel
VHL
von Hippel–Lindau protein
ZIP
ZRT/IRT-like protein

Keywords

Iron metabolism
Iron uptake
Transferrin
ISC biogenesis
Mitochondrion

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