40/41 - Iron Uptake & Distribution Flashcards
TRANSFERRIN
Function
Fe2+ –FPN1–> Fe2+ in Blood –HEPH–> Fe3+
CARRIER OF IRON
though the Plasma / ECF
BINDS ONLY Fe3+
2 Fe3+ irons per transferrin
What happens when
IRP binds IRE in the 5’-UTR region?
5=stop
Iron Depleted Cells
VVVVV
BLOCK ribosomal binding & interrrupt protein synthesis
VVVVVV
translational REPRESSION
of FERRITIN
LESS IRON STORAGE
Hemochromatosis
Excessive ABSORPTION of dietary IRON
&
ALTERED Iron Storage
Iron storage disorder
treated by:
reducing dietary iron / avoiding High VIT C Intake
blood removal
How does TRANSFERRIN assist IRON transport?
- *Fe3+ is relatively
- INSOLUBLE*and isReactive**
Transferrin:
INCREASES SOLUBILITY
&
reduces its REACTIVITY & iron-mediated redox toxicity
Morphological Adaptations
that occur during IRON DEFICIENCY
In order to maximize capacity of small intestine
overall increased surface area
INCREASED
MUCOSAL THICKNESS
VILLUS LENGTH + WIDTH
ENHANCED:
MITOSIS of stem cells in crypts
Iron
General Info
SECOND most abundant metal, after Aluminum
Main Role:
Enzymes involved in DNA Replication / repair / translation
rely on iron in the Fe-S Clusters & Heme
Second Main Role:
oxygen-binding characteristic of HEME
crucial for the oxygen-carrying capacity of hemoglobin + myoglobin
Bacteria & Cancer cells LOVE IRON
What causes
HYPOXIA?
hypoxia –> direct effect on gut –>
Increase Iron absorption & High Hematocrit (# RBC)
SMOKING
CO2 –> hemoglobin –> outcompetes oxygen
HIGH ALTITUDE
takes 12 weeks for haematological adaptation
- *CD163**
- *FUNCTION**
Expresed by MACROPHAGES
specialised to take in
HEMOGLOBIN in complex w/ HAPTOGLOBIN
Haptoglobin binds free Hg
MALARIA & FPN/HEPCIDIN
Malaria parasites invade RBCs –> consume Hemoglobin
& severely disrupt iron regulation in humans
Iron Supplementation –> MADE DISEASE WORSE
VVVV
UPREGULATE Hepcidin
VVVV
_decrease in Ferroportin expression_
VVVV
less protection against MALARIA
FPN protects RBC’s
against OXIDATIVE STRESS + Malaria Infaction
Function of HEME OXYGENASE
After HEME IRON is endocytized into an endosome
LIBERATES IRON (Fe2+) from HEME
inside an endosome
HEPH
Location / Function
HEPHAESTIN @ Basolateral Membrane = BLM
of the duodenum
- *FERROOXIDASE**
- *Fe2+ –oxidation–> Fe3+**
Transferrin will ONLY bind Fe3+
TRANSFERRIN - TFR1
Internalization PATHWAY
Transferrin-TFR1 is internalized via
CLATHRIN-MEDIATED ENDOCYTOSIS
VVVVV
Fe3+ is liberated from transferrin,
as a result of drop in pH –> 5.5 within the vescicle
proton pump on endosome –> acidifies endosome
VVVVV
STEAP3
Fe3+ –reduced–> Fe2+
VVVVV
DMT1
transports Fe2+ into the cytoplasm
Ferritin IMPORT
UNKNOWN MECHANISM
Ferritin –> Duodenal Enterocyte –> Lysosome
VVVVV
CIP / LIP
- *HEME IRON**
- *Compunds + Functions**
HemoGlobin + MyoGlobin
oxygen transport
- *Cytochrome ABC + P450**
- *ETC** - oxidative energy + drug metabolism
Catalase + Peroxidase
electron acceptors
TFR1
FUNCTION
Transferrin Receptor 1
membrane bound
Binds to IRON-BOUND TRANSFERRIN @ phys. PH
not for APO-transferrin = ironfree transferrin
VVVVV
to be internalized via clathrin mediated endocytosis
What is the MAIN UTILIZERS of
Circulating Iron
BONE MARROW** + **Muscle MYOGLOBIN
Humans ONLY ABSORB:
1-2 mg of iron per day
(from duodenum)
which compensates for the iron loss
which is 1-2 mg /day from sloughed cells / menstration
NHE
Function / location
Sodium / Hydrogen Exchanger
@ Brush-Border of duodenum enterocytes
PROVIDES PROTON (H+) for DMT
pumps Na+ in // H+ out
proton coupled w/ Fe2+ –> DMT1 –> enter cell
- *Ceruloplasmin**
- *Location + Function**
FERROOXIDASE
that is located everywhere
EXCEPT** for the **duodenem (hephaestin)
Fe2+ –oxidation–> Fe3+
to be bound by TRANSFERRIN in the BLOOD
Hepcidin
Synthesis
encoded by HAMP GENE
which is highly expressed in the LIVER
is the MASTER REGULATOR of systemic iron metabolism
- *What does IRON SUPPLMENTATION** do to
- *FERROPORTIN?**
SUPPRESS ITS ACTIVITY
Iron Supplementation
VVVV
MORE Hepcidin
VVVV
_downregulate FPN_
Oxidative stress / More Severe Malaria infection
How is NTBI
UPTAKEN?
Non-Transferrin-Bound Iron
there are 3 cellular membrane transporters involved:
DMT1 // ZIP14 // ZIP8
Bring NTBI –> Cells
still requires a ferrireductase to reduce Fe3 –> Fe2
before internalization
How is Hepcidin Expression REGULATED
by HYPOXIA / ANEMIA & Erythroid Factors
Anemia / Hypoxia
VVVV
INCREASE in Erythopoietin = EPO expression
VVVVV
ERYTHROPOIESIS is STIMULATED
VVVVV
decreases HEPCIDIN gene expression
VVVVV
MORE IRON for HEME / RBC PRODUCTION
What happens when
IRP binds IRE in the 3’-UTR region?
“3THREE = inCREEEase” mRNA translation
Iron DEPLETED CELLS
VVVVV
stabilize the transcript
PREVENT mRNA degradation
VVVV
INCREASE mRNA Translation & Protein Synthesis
of TfR1
to stimulate acquisition of IRON
Function & Location of
DCYTB
FerriREDUCTASE @ the Brush-Border Membrane
duodenal cytochrome B = DCYTB
REDUCES NON-HEME IRON
Fe3+ –> Fe2+
VVVV
DMT1
at the expense of a intracellular Ascorbate = Vit C
- *Iron-Sulfer Clusters**
- *ROLE**
Mitochondrial Electron Transport
Fe-S
Oxidation-Reduction Reactions
FERROPORTIN = FPN
Function / Location
Only known
Cellular EXPORTER of UNBOUND IRON
- *Hepcidin** –> binds to ferroportin –> endocytosis + degradation
- prevents iron EGRESS from the cell*
found mostly in :
enterocytes in duodenum // hepatocytes // macrophages
What INCREASES
Iron Absorption?
HEME IRON
>> better absorbed vs non-heme iron
low pH
enhances iron absorption
- *ERYTHPOIESIS** stimulation
- *blood loss / acute hemolysis**
- *HYPOXIA**
- -> hypoxia exerts a direct effect on the GUT
PREGNANCY
- *Ferritin & Hemosiderin**
- *Iron Stores**
20-30% of Iron in the body
inside Hepatocytes** & **RES Macrophages
3mg of iron is bound to transferrin
but plasma transferrin compartment functions as TRANSIT
flows about 20mg of iron/day
Iron FUNCTION as a
COFACTOR
Cytochrome
in ETC helps transport electron –> O2
- *CYP450**
- *Oxidative degradation** of drugs
Mitochondria
ACONITASE (Fe-S) as TCA enzyme
Citrate –> Isocitrate
What BLOCKS iron absorption?
PHYTATES
TANNINS
ANTACIDS
LIP / CIP / FREE IRON
after cellular iron UPTAKE –> LIP
Pool of IRON complexed w/ Low affinity ligands
Citrate / ATP / AA’s / Vit C / unknown chaperones
IRON2-Glutathione = dominant componant of the pool
<5% of total cellular iron
the dynamic compartment that supplies iron to the MITCHONDRION for
HEME + Fe-S Clusters
excess iron –> stored in FERRITIN
MITOFERRIN 1 & 2
Function
specialized transporters that
- *Move IRON** (usually from the LIP/CIP)
- -> the MITOCHONDRIA
where Iron can assist in:
cellular respiration
&
synthesis of Fe-S clusters + HEME
What is an
IRE?
Iron-Responsive Element
conserved hairpin structures of mRNA (25-30 NT)
that bind to
IRP 1 // IRP 2
- *FLVCR1B Pathway**
- *Function**
Another pathway for the SECRETION OF HEME
EMERGENCY VALVE
to prevent heme overload
&
Route for MACROPHAGES
to directly supply HEME –> developing erythroblasts
TFR1
Location
Transferrin Receptor 1
expressed by ALL iron-requiring cells
but it’s levels of expression VARIES GREATLY
Highly Expressed on:
immature erythroid cells // rapidly dividing cells
placental tissue
STEAP3
Function / Location
FerriREDUCTASE
located inside the endosome
Fe3+ –reduced–> Fe2+
which is then brought –> cytoplasm by DMT1
Factors that ALTER
Iron Digestion / Absorption
Individual’s Iron Status
Level of dietary iron consumption
TYPE of iron in foods
Amount of STOMACH ACID for digestion
Dietary factors enhance or inhibit absorption
4 Major Pathways
in HEPCIDIN REGULATION
- *IRON Stores / Status / Dietary**
- *HIGH IRON** –> MORE HEPCIDIN
- -> less FPN –> restrict iron availability
INFLAMMATION** / **INFECTION
induces HAMP –> MORE HEPCIDIN
- HYPOXIA / ANEMIA*
- decrease HEPCIDIN*
- ERYTHROID FACTORS*
- decrease HEPCIDIN*
How is Intracellular IRON (Fe2+)
transported to the BLOOD?
RAPIDLY transferred across the
Basolateral Membrane = BLM
by FPN1
when body iron demands are HIGH
VVVVV
Fe2+ –> BLOOD
VVVVV
HEPH
Fe2+ –oxidized–> Fe3+
VVVV
TRANSFERRIN
Iron DISTRIBUTION
What is the most abundant form of iron?
- *HEMOGLOBIN**
- *60-70%** iron in the body
body has around 5g of iron
Functional Iron
Hemoglobin > myoglobin > enzymes
Storage:
Ferritin > hemosiderin = 20-30%
in hepatosites / RES macrophages
Mutations in the FERROPORTIN GENE
do what?
Ferroportin = only iron exporter
BLM of duodenal enterocytes / RES macrophages / hepatocytes / placental cells
Affect IRON EXPORT from MACROPHAGES
VVVVV
TYPE 4 HEMOCHROMATOSIS
How is HEME iron Absorbed?
Heme = more soluble
ENDOCYTOSIS
intestine –> membrane
VVVVV
ENDOSOME
VVVVV
iron is then liberated from heme within the endosome by
HEME OXYGENASE = HO
VVVVV
Fe2+ for CIP/LIP
How is Hepcidin Expression REGULATED
by INFLAMMATION?
Inflammation:
–> IL-6** + other **CYTOKINES
VVVV
JAK1/2 - STAT3 activation
VVVV
HAMP expression
VVVV
Hepcidin –> restricts iron availability
HEPCIDIN
FUNCTION
MASTER REGULATOR of systemic iron metabolism
regulates the systemic flux of iron by
modulating the levels of FERROPORTIN
Hepcidin –> Ferroportin’s Extracellular domain
VVVV
ENDOCYTOSIS
VVVV
DEGRADATION OF FERROPORTIN (IRON)
preventing iron egress from the cells
Things that INHIBIT
IRON UPTAKE
chronic use of PPI’s –> INCREASE pH (less absorbed)
H.Pylori / Celiac’s Disease for non-heme
Full body stores of Iron
- *IRON CHELATORS**
- *POLYOPHENOL -** tea / coffee / lagumes
- *OXALATE** - spinach / rhubarb / chocolate
- *PHYTATES** / TANNINS - wheat / teas
- *Egg Yolk / Fiber / Oxalates**
- *CARBONATES - Calcium for heme**
Things that PROMOTE
IRON UPTAKE
Duodenal lumen –> MUCOSA (lining–>blood)
Amino Acids / Animal Proteins
VITAMIN C
HCL / Organic Acids
low pH
Sugars –> form iron chelates
fructose / sorbital
- *Link between**
- *IMMUNITY & IRON METABOLISM**
Infections / Inflammation
VVVVV
IL6 / Cytokines that
INDUCE HEPCIDIN SYNTHESIS
less iron availability for Bacteria/pathogens/cancer growth
bacterial pathogens / cancer require iron to multiply
Dietary Iron Absorption
& Where?
1-2 mg of Iron from diet/day
some is lost through cell sloughing & bleeding
bone marrow = main consumer
- *OCCURS @ SMALL INTESTINE**
- *duodenum / proximal jejunem**
IRP1
FUNCTION
Iron-Regulatory Protein
- *Ubiquitously expressed** cytosol
- *IRON-SULFUR** protein
Iron Replete / Enough Iron:
IRP1 acts as an ACONITASE
lacks _RNA binding activity_
in the absence of iron –> binds to IRE
more TfR1 & less _ferritin_ synthesis
more IRON acquisition & less iron storage
- *4 General Pathways** for individual cells to
- *INTERNALIZE IRON**
- *TFR1**
- *Transferrin** bound iron = MOST COMMON
DMT1 & ZIP14+8
bring in NTBI’s
CD163** + **LRP1 + HRG1
bring in Haptoglobin + Hg /// heme + hemopexin
SCARA5
internalizes Ferritin
Systemic IRON METABOLISM PATHWAY
HIGH IRON
High Iron / FERRITIN stores –> SMAD Signaling
HAMP TRANSCRIPTION
VVVVV
upregulates HEPCIDIN production
VVVVV
hepcidin INHIBITS Ferroportin expression
VVVVV
less FPN to intake Iron back into the:
systemic iron pool
from macrophages / enterocytes / hepatocytes
DMT1
Function / Location
Divalent Metal-Ion Transporter 1
@ Brush Border of Duodenal Enterocytes
Proton-Coupled Uptake of Fe2+ Ferrous
with the help of
NHE = sodium/hydrogen exchanger
that provides the Proton
How is TFR1 + APO-Transferrin
RECYCLED?
Apotransferrin = unbound/no-irontransferrin
due to the pH difference (low 5.5 pH)
they are
recycled back to the CELL SURFACE
where the pH is physiological
transferrin can make around 100-200 cycles of iron transport
- *HEME**
- *Food Sources**
Animal origin:
- *MEAT / FISH / POULTRY**
- less dominant in standard diet = 10%*
- BETTER ABSORBEDvs than non-heme iron***
- *5-25%** are absorbed
Iron-porphyrin Prosthetic Group
Hemoglobin / myoglobin / cytochromes
How does VITAMIN C
INDIRECTLY assist Non-Heme Absorption?
ASC –> Ascorbyl Radical (AR)
donates an ELECTRON for DCYTB
Fe3+ –> Fe2+
ferrireductase
Where are IRE’s LOCATED?
TFR1 mRNA
has multiple IRE’s within 3’UTR
PREVENT Degredation –> more TFR1
H/L Ferritin mRNA
contain a SINGLE IRE in their 5’UTR
repress translation / protein synthesis –> less Ferritin
IRP2
FUNCTION
iron-regulatory protein
- *only** functions as a:
- *RNA BINDING PROTEIN**
- *Replete Iron / Enough Iron**
- DEGRADED / not used*
“IRP2 = NOT YOU”
How is NON-HEME Iron Absorbed?
DCYTB = FerriReductase
Fe3+ –> Fe2+
VVVVV
DMT1 = symporter
VVVVV
Fe2+ enters the membrane
CIP / LIP
Ferritin
Function
MAJOR INTRACELLULAR IRON STORAGE PROTEIN
stores ~4,500 iron atoms
LIVER - 60% of ferritin in body
Muscle / Reticuloendothelial - 40%
Ferritin is always being loss
due to the apical cells –> sloughed off / exfoliated
How is Hepcidin Expression REGULATED
by IRON STATUS in Hepatocytes?
HIGH IRON
VVVVV
BMP6 RECEPTOR** + **HJV
bone morphogenic protein 6 // haemojuvelin
VVVVV
downstream SMAD signaling
VVVVV
Nucleus —> HAMP –> more hepcidin
reduction in iron availability
Non-Heme Iron
Food Sources
Vegetable Origin
cereal / veggies / molasses
90% of DIETARY iron
but is HIGHLY INSOLUBLE
only 2-5% is absorbed
Transferrin / Ferritin / Enzymes with iron @ active site
Iron-sulphur proteins
IRON
TOXICITY
Accidental Iron Overdose = MOST COMMON cause of poisining deaths in children
High Iron content in prenatal multivitamins
toxicity is a function of the # of iron per KG of weight
so children can QUICKLY reach a toxic dose
–> destroys LINING OF GI TRACT
Hemochromatosis
Where does MOST of the iron RECYCLED?
RES MACROPHAGES in the SPLEEN
Reticuloendothelial System
Recycle 10-20x more IRON vs intestine absorbs
- *RBC / Heme –> HO1** –>
- *IRON via ferroportin
- -> transferrin**
How is IRON LOSS?
After Iron –> epithelial cells:
transported for circulation
or
sequestrated as Ferritin
last only 2 DAYS before being
USED or SHED into intestinal lumen
lost by
- *EXFOLIATION OF INTESTINAL EPITHELIUM**
- *1-2mg / day**
What do IRP1 & IRP2
have in COMMON?
in the absence of iron
VVVV
binds to IRE
VVVV
more TfR1 –> more IRON acquisition from plasma
&
steric blockade to FERRITIN mRNA translation
—> obsolete iron storage
NON-Heme Fe2+
Source / Absorpition
Fe2+ = FERROUS
- *MORE SOLUBLE** than Ferric Fe3+
- LESS ABUNDANT though,*
- *Fe3+ is reduced to Fe2+ for transport**
How does VITAMIN C
DIRECTLY assist Non-Heme Absorption?
just a HYPOTHESIS
ASC crosses the membrane –> EXTRACELLULAR
reacts DIRECTLY w/ Fe3+
to produce Fe2+
NON-Heme Iron
Compounds + Functions
NAD Dehydrogenase
Xanthine Oxidase
Ribonucleotide Reductase
Succinate Dehydrogenase
- *NON-Heme Fe3+**
- *Source / Absorption**
Fe3 = FERRIC
Found in both meat + plant foods
- *MORE DOMINANT form of Non-Heme IRON**
- needs to be converted to ferrous Fe2+ before transport*
HIGHLY INSOLUBLE
only about 2% absorbed from meal
FPN1
Function / Location
Ferroportin 1 @ Basolateral Membrane = BLM
on all tissues that export iron –> plasma
rapid IRON EXPORTER
Fe2+ –> BLOOD
CIP/intracellular Iron –> into the blood
