Iron Metabolism Flashcards
What is the Fenton reaction
Fe2+ + H2O2 → Fe3+ + OH- + OH*
- Prevents accumulation of excess iron and oxidative radicals
What are manifestations/symptoms of iron deficiencies (mostly nutritional) and of iron overload (hereditary or acquired)?
Iron deficiency:
- Anemia
- Growth defects
- Cognitive impairment
- Immune defects
- Heart disease
Iron overload:
- Liver disease
- Heart disease
- Diabetes
- Arthitis
- Osteoporosis
How is iron distributed in the human body?
1-2mg absorbed/day in enterocytes → Plasma Transferrin ~3mg (to sequester the toxic free iron) → Bone marrow for erythropoiesis (~300 mg at steady state, ~20-30mg/day used)
- Muscles ~ 300mg (primarily myoglobin)
- Liver ~ 1000mg *primarily in ferritin
- RBCs ~ 2400 mg (in hemoglobin)
Macrophages (spleen and liver) recycle old RBCs ~600mg
Loss of ~ 1-2 mg/day → sweat, hair, nails, blood loss
What is transferrin? (main features)
Plasma iron transporter/carrier, at steady state it contains ~ 3 mg of iron
- Helps replenish the iron pool ~ 10x/day
- Monomeric glycoprotein of 80 kDa delivers irons to tissues
- Binds 2x Fe3+ atoms with high affinity (Kd = 10^-23 at neutral pH, drops at lower pH)
- Under physiological conditions, only 30% is saturated with iron → leaves a buffer for iron excreted from other tissues
What is the major site of dietary iron absorption in mammals?
Duodenum
Mature enterocytes in microvillar tips, derived from precursor crypt cells
Inorganic iron is internalized from the lumen by the apical transporter DMT1, and exported to the bloodstream via the basolateral transporter FERROPORTIN
How is transferrin-bound iron taken up by cells?
Holo-transferrin = bound to Fe
- TfR1 binds to holo-transferrin (high affinity)
- Clathrin-coated internalization → endocytosis
- In endosomes, pH drops → iron dissociates from TfR1
- Free iron is transported through to the cytosol through DMT1 (ubiquitously expressed)
- Iron is transported to the mitochondria to iron-utilizing proteins
- When excess in the cells → stored within ferritin inside the cells
- Some excess can also be released to circulation (safety mechanism) via ferroportin (Ubiquitously expressed)
Which 3 genes are regulated at the transcriptional level by IRE?
(IRE/IRP system)
TfR1 → multiple IREs in the 3’ UTR
Ferritin → 1x IRE in the 5’ UTR
Ferroportin → 1x IRE in the 5’ UTR
In low iron:
- Prevent TfR1 degradation → increase iron uptake
- Block Ferritin transcription → decrease iron storage
- Block ferroportin transcription → decrease iron efflux
High iron:
- Increase TfR1 degradation → decrease iron uptake
- Allow Ferritin transcription → increase iron storage
- Allow ferroportin transcription → increase iron efflux
What is the mechanism of hepcidin?
Hepcidin binds to ferroportin:
1. Induces ferroportin internalization and degradation by lysosomes
2. occludes iron efflux
*Ferroportin is responsible for iron efflux
*Induced under high iron conditions
Where is Hepcidin expressed?
in High iron and inflammation → expressed in the liver → goes to enterocytes (prevent absorption) and macrophages (prevent recycling)
What pathways regulate hepcidin expression are the transcriptional level?
- iron signaling
- EREFE = erythropoietic inhibition of BMP6-mediated signaling
- HAMP = Hepcidin
- BMP =
- BMP6 binds to BMP receptor → SMAD → BMP-Response Element 1 in the promotor of HAMP - Inflammation signaling
- IL-6 binds to IL-6 receptor → JAK/STAT (STAT phosphorylation) → binds STAT3-BS in promotor
*Cross-talk between both pathways, Inflammation pathways requires iron signaling
What are the disorders of iron overload?
- Hereditary Hemochromatosis (HH)
- Secondary (transfusional) iron overload
- Sideroblastic anemias, sickle cell anemias, thalassemias
What is the pathogenesis of Hereditary Hemochromatosis /how does it develop?
- Hyperabsorption of dietary iron (rate may reach 8-10 mg/day)
- Prograssive saturation of plasma Tf and buildup of non-transferrin bound iron (NTBI → toxic)
- Uptake of NTBI by parenchymal cells, development of tissue iron overload (liver, pancreas), usually in the 4th decade of life
*If happens earlier, can be really dangerous
What are possible complications of HH
- Diabetes
- HH was first described in 1865 as “bronze diabetes” by Armand Trousseau
- In 1890, Friedrich Daniel von Recklinghausen recognized that “bronze diabetes” was caused by pancreatic iron overload - Liver disease → fibrosis, cirrhosis, hepatocellular cancer
- Arthritis, osteoporosis
- Cardiomyopathy, hypogonadism
→ commonly associated with juvenile hemochromatosis (JH), which develops in the late teens or early twenties
Explain the HH paradox.
Tissue macrophages and intestinal enterocytes
are iron-deficient, in spite of systemic iron overload
The pathogenesis of HH is linked to the inability of macrophages and enterocytes to retain iron
→ Hepcidin deficiency explains the HH paradox
What is the genetic explanation of HH?
Of a specific C282Y mutation of HFE.
The most common genetic disease in populations of
Northern European ancestry
It possibly originated in central Europe at around 4000 BC, when humans switched from iron-rich meat-based diet to iron-poor agricultural dietary sources
- The estimated frequency of HFE homozygocity is 1:200
C282Y but not all carriers develop iron overload
- The development of iron overload in HFEC282Y carriers depends on gender, race, genetic factors (modifier genes), epigenetic alterations, environmental factors (alcohol consumption)
