Editing Iron (section)

==Biological and pathological role==
{{Main|Iron in biology}}

Iron is required for life.<ref name="lpi" /><ref>{{cite book |last1=Dlouhy |first1=Adrienne C. |last2=Outten |first2=Caryn E. |chapter=The Iron Metallome in Eukaryotic Organisms |editor1-first=Lucia |editor1-last=Banci |series=Metal Ions in Life Sciences |volume=12 |pages=241–78 |title=Metallomics and the Cell |date=2013 |publisher=Springer |isbn=978-94-007-5560-4|doi=10.1007/978-94-007-5561-1_8|pmid=23595675 |pmc=3924584}} electronic-book {{ISBN|978-94-007-5561-1}}</ref><ref>
{{cite book |first1=Gereon M. |last1=Yee |first2=William B. |last2=Tolman |editor=Peter M.H. Kroneck |editor2=Martha E. Sosa Torres |title=Sustaining Life on Planet Earth: Metalloenzymes Mastering Dioxygen and Other Chewy Gases |chapter=Transition Metal Complexes and the Activation of Dioxygen |series=Metal Ions in Life Sciences |volume=15 |year=2015 |publisher=Springer |pages=131–204 |doi=10.1007/978-3-319-12415-5_5 |pmid=25707468|isbn=978-3-319-12414-8 }}
</ref> The [[iron–sulfur cluster]]s are pervasive and include [[nitrogenase]], the enzymes responsible for biological [[nitrogen fixation]]. Iron-containing proteins participate in transport, storage and use of oxygen.<ref name="lpi" /> Iron proteins are involved in [[electron transfer]].{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}}
[[File:Heme B.svg|thumb|Simplified structure of [[Heme|Heme B]]; in the protein additional [[ligand]](s) are attached to Fe.]]

Examples of iron-containing proteins in higher organisms include hemoglobin, [[cytochrome]] (see [[high-valent iron]]), and [[catalase]].<ref name="lpi" /><ref>{{Cite book| first1 = S.J.|last1 = Lippard|first2 = J.M.|last2 = Berg|title = Principles of Bioinorganic Chemistry|publisher = University Science Books|place = Mill Valley|date = 1994|isbn = 0-935702-73-3}}</ref> The average adult human contains about 0.005% body weight of iron, or about four grams, of which three quarters is in hemoglobin—a level that remains constant despite only about one milligram of iron being absorbed each day,{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}} because the human body recycles its hemoglobin for the iron content.<ref>{{Cite journal
| last1 = Kikuchi | first1 = G.
| last2 = Yoshida | first2 = T.
| last3 = Noguchi | first3 = M.
| doi = 10.1016/j.bbrc.2005.08.020
| title = Heme oxygenase and heme degradation
| journal = Biochemical and Biophysical Research Communications
| volume = 338
| issue = 1
| pages = 558–67
| year = 2005
| pmid = 16115609
}}</ref>

Microbial growth may be assisted by oxidation of iron(II) or by reduction of iron(III).<ref>{{cite book |doi=10.1515/9783110589771-006 |chapter=Contents of Volumes in the Metal Ions in Life Sciences Series |title=Metals, Microbes, and Minerals - the Biogeochemical Side of Life |year=2021 |pages=xxv-xlvi |publisher=De Gruyter |isbn=9783110589771|s2cid=196704759 }}</ref>

===Biochemistry===
Iron acquisition poses a problem for aerobic organisms because ferric iron is poorly soluble near neutral pH. Thus, these organisms have developed means to absorb iron as complexes, sometimes taking up ferrous iron before oxidising it back to ferric iron.<ref name="lpi" /> In particular, bacteria have evolved very high-affinity [[wikt:sequester|sequestering]] agents called [[siderophore]]s.<ref>{{Cite journal |pmid=7592901 |doi=10.1074/jbc.270.45.26723 |date=1995 |last1=Neilands |first1=J.B. |title=Siderophores: structure and function of microbial iron transport compounds |volume=270 |issue=45 |pages=26723–26 |journal=The Journal of Biological Chemistry |doi-access=free}}</ref><ref>{{Cite journal |doi=10.1146/annurev.bi.50.070181.003435 |title=Microbial Iron Compounds |date=1981 |last1=Neilands |first1=J.B. |journal=Annual Review of Biochemistry |volume=50 |pages=715–31 |pmid=6455965|issue=1}}</ref><ref>{{Cite journal| doi=10.1023/A:1020218608266 |date=2002 |last1=Boukhalfa |first1=Hakim |last2=Crumbliss |first2=Alvin L. |journal=BioMetals |volume=15 |issue=4 |pages=325–39 |pmid=12405526 |title=Chemical aspects of siderophore mediated iron transport |s2cid=19697776}}</ref>

After uptake in human [[cell (biology)|cells]], iron storage is precisely regulated.<ref name="lpi" /><ref>{{Cite journal |title=Tumor necrosis factor-α-induced iron sequestration and oxidative stress in human endothelial cells |last11=Nakanishi |first11=T. |last10=Suzuki |first10=K. |first9=H. |last9=Eguchi |first8=M. |last8=Izumi |first7=Y. |last7=Hasuike |first6=K. |last6=Miyagawa |first5=R. |last5=Moriguchi |first4=K. |last4=Ito |first3=Y. |last3=Otaki |first2=T. |last2=Ookawara |first1=M. |last1=Nanami |pmid=16224057 |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |date=2005 |volume=25 |issue=12 |pages=2495–501 |doi=10.1161/01.ATV.0000190610.63878.20 |doi-access=free}}</ref> A major component of this regulation is the protein [[transferrin]], which binds iron ions absorbed from the [[duodenum]] and carries it in the [[bloodstream|blood]] to cells.<ref name="lpi" /><ref>{{Cite journal|doi=10.1371/journal.pbio.0000079|title=How Mammals Acquire and Distribute Iron Needed for Oxygen-Based Metabolism|date=2003|last=Rouault|first = Tracey A.|author-link=Tracey Rouault|journal=PLOS Biology |volume=1 |issue=3 |pages=e9 |pmid=14691550|pmc=300689 |doi-access=free }}</ref> Transferrin contains Fe<sup>3+</sup> in the middle of a distorted octahedron, bonded to one nitrogen, three oxygens and a chelating [[carbonate]] anion that traps the Fe<sup>3+</sup> ion: it has such a high [[Stability constants of complexes|stability constant]] that it is very effective at taking up Fe<sup>3+</sup> ions even from the most stable complexes. At the bone marrow, transferrin is reduced from Fe<sup>3+</sup> to Fe<sup>2+</sup> and stored as [[ferritin]] to be incorporated into hemoglobin.{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}} <!--Inorganic iron contributes to redox reactions in the [[iron–sulfur cluster]]s of many [[enzyme]]s, such as [[nitrogenase]] (involved in the synthesis of [[ammonia]] from [[nitrogen]] and [[hydrogen]]) and [[hydrogenase]]. Non-heme iron proteins include the [[enzymes]] [[methane monooxygenase]] (oxidizes [[methane]] to [[methanol]]), [[ribonucleotide reductase]] (reduces [[ribose]] to [[deoxyribose]]; [[DNA replication|DNA biosynthesis]]), [[hemerythrin]]s ([[oxygen]] transport and fixation in [[marine invertebrates]]) and purple [[acid phosphatase]] ([[hydrolysis]] of [[phosphate]] [[ester]]s).-->

The most commonly known and studied [[bioinorganic chemistry|bioinorganic]] iron compounds (biological iron molecules) are the [[heme proteins]]: examples are [[hemoglobin]], [[myoglobin]], and [[cytochrome P450]].<ref name="lpi" /> These compounds participate in transporting gases, building [[enzymes]], and transferring [[electron]]s.{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}} [[Metalloproteins]] are a group of proteins with metal ion [[cofactor (biochemistry)|cofactors]]. Some examples of iron metalloproteins are [[ferritin]] and [[rubredoxin]].{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}} Many enzymes vital to life contain iron, such as [[catalase]],<ref name="Boon_b">{{cite web |vauthors=Boon EM, Downs A, Marcey D |title=Proposed Mechanism of Catalase |work=Catalase: H<sub>2</sub>O<sub>2</sub>: H<sub>2</sub>O<sub>2</sub> Oxidoreductase: Catalase Structural Tutorial |url=https://biology.kenyon.edu/BMB/Chime/catalase/frames/cattx.htm#Proposed%20Mechanism%20of%20Catalase |access-date=2007-02-11}}</ref> [[lipoxygenases]],<ref>{{cite journal |vauthors=Boyington JC, Gaffney BJ, Amzel LM |title=The three-dimensional structure of an arachidonic acid 15-lipoxygenase |journal=Science |volume=260 |issue=5113 |pages=1482–86 |year=1993 |pmid=8502991 |doi=10.1126/science.8502991 |bibcode=1993Sci...260.1482B}}</ref> and [[IRE-BP]].<ref>{{cite journal |last1=Gray |first1=N.K. |last2=Hentze |first2=M.W. |title=Iron regulatory protein prevents binding of the 43S translation pre-initiation complex to ferritin and eALAS mRNAs |journal=EMBO J. |volume=13 |number=16 |pages=3882–91 |date=August 1994 |pmc=395301 |pmid=8070415 |doi=10.1002/j.1460-2075.1994.tb06699.x}}</ref>

Hemoglobin is an oxygen carrier that occurs in [[red blood cell]]s and contributes their color, transporting oxygen in the arteries from the lungs to the muscles where it is transferred to [[myoglobin]], which stores it until it is needed for the metabolic oxidation of [[glucose]], generating energy.<ref name="lpi" /> Here the hemoglobin binds to [[carbon dioxide]], produced when glucose is oxidized, which is transported through the veins by hemoglobin (predominantly as [[bicarbonate]] anions) back to the lungs where it is exhaled.{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}} In hemoglobin, the iron is in one of four [[heme]] groups and has six possible coordination sites; four are occupied by nitrogen atoms in a [[porphyrin]] ring, the fifth by an [[imidazole]] nitrogen in a [[histidine]] residue of one of the protein chains attached to the heme group, and the sixth is reserved for the oxygen molecule it can reversibly bind to.{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}} When hemoglobin is not attached to oxygen (and is then called deoxyhemoglobin), the Fe<sup>2+</sup> ion at the center of the [[heme]] group (in the hydrophobic protein interior) is in a [[Spin states (d electrons)#High-spin and low-spin systems|high-spin configuration]]. It is thus too large to fit inside the porphyrin ring, which bends instead into a dome with the Fe<sup>2+</sup> ion about 55 picometers above it. In this configuration, the sixth coordination site reserved for the oxygen is blocked by another histidine residue.{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}}

When deoxyhemoglobin picks up an oxygen molecule, this histidine residue moves away and returns once the oxygen is securely attached to form a [[hydrogen bond]] with it. This results in the Fe<sup>2+</sup> ion switching to a low-spin configuration, resulting in a 20% decrease in ionic radius so that now it can fit into the porphyrin ring, which becomes planar.{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}} Additionally, this hydrogen bonding results in the tilting of the oxygen molecule, resulting in a Fe–O–O bond angle of around 120° that avoids the formation of Fe–O–Fe or Fe–O<sub>2</sub>–Fe bridges that would lead to electron transfer, the oxidation of Fe<sup>2+</sup> to Fe<sup>3+</sup>, and the destruction of hemoglobin. This results in a movement of all the protein chains that leads to the other subunits of hemoglobin changing shape to a form with larger oxygen affinity. Thus, when deoxyhemoglobin takes up oxygen, its affinity for more oxygen increases, and vice versa.{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}} Myoglobin, on the other hand, contains only one heme group and hence this cooperative effect cannot occur. Thus, while hemoglobin is almost saturated with oxygen in the high partial pressures of oxygen found in the lungs, its affinity for oxygen is much lower than that of myoglobin, which oxygenates even at low partial pressures of oxygen found in muscle tissue.{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}} As described by the [[Bohr effect]] (named after [[Christian Bohr]], the father of [[Niels Bohr]]), the oxygen affinity of hemoglobin diminishes in the presence of carbon dioxide.{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}}

[[File:Carboxyhemoglobin from 1AJ9.png|thumb|right|A heme unit of human [[carboxyhemoglobin]], showing the [[carbonyl ligand]] at the apical position, ''trans'' to the histidine residue<ref>{{cite journal | journal = Acta Crystallogr. D | title = Human Carboxyhemoglobin at 2.2 Å Resolution: Structure and Solvent Comparisons of R-State, R2-State and T-State Hemoglobins |author1=Gregory B. Vásquez |author2=Xinhua Ji |author3=Clara Fronticelli |author4=Gary L. Gilliland | doi = 10.1107/S0907444997012250 | pmid = 9761903 | volume = 54 | issue = 3 | pages = 355–66 | year = 1998| doi-access = free | bibcode = 1998AcCrD..54..355V }}</ref>]]
[[Carbon monoxide]] and [[phosphorus trifluoride]] are poisonous to humans because they bind to hemoglobin similarly to oxygen, but with much more strength, so that oxygen can no longer be transported throughout the body. Hemoglobin bound to carbon monoxide is known as [[carboxyhemoglobin]]. This effect also plays a minor role in the toxicity of [[cyanide]], but there the major effect is by far its interference with the proper functioning of the electron transport protein [[cytochrome a]].{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}} The cytochrome proteins also involve heme groups and are involved in the metabolic oxidation of glucose by oxygen. The sixth coordination site is then occupied by either another imidazole nitrogen or a [[methionine]] sulfur, so that these proteins are largely inert to oxygen—with the exception of cytochrome a, which bonds directly to oxygen and thus is very easily poisoned by cyanide.{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}} Here, the electron transfer takes place as the iron remains in low spin but changes between the +2 and +3 oxidation states. Since the reduction potential of each step is slightly greater than the previous one, the energy is released step-by-step and can thus be stored in [[adenosine triphosphate]]. Cytochrome a is slightly distinct, as it occurs at the mitochondrial membrane, binds directly to oxygen, and transports protons as well as electrons, as follows:{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}}

:4 Cytc<sup>2+</sup> + O<sub>2</sub> + 8H{{su|p=+|b=inside}} → 4 Cytc<sup>3+</sup> + 2 H<sub>2</sub>O + 4H{{su|p=+|b=outside}}

Although the heme proteins are the most important class of iron-containing proteins, the [[iron–sulfur protein]]s are also very important, being involved in electron transfer, which is possible since iron can exist stably in either the +2 or +3 oxidation states. These have one, two, four, or eight iron atoms that are each approximately tetrahedrally coordinated to four sulfur atoms; because of this tetrahedral coordination, they always have high-spin iron. The simplest of such compounds is [[rubredoxin]], which has only one iron atom coordinated to four sulfur atoms from [[cysteine]] residues in the surrounding peptide chains. Another important class of iron–sulfur proteins is the [[ferredoxin]]s, which have multiple iron atoms. Transferrin does not belong to either of these classes.{{sfn|Greenwood|Earnshaw|1997|pp=1098–104}}

The ability of sea [[mussel]]s to maintain their grip on rocks in the ocean is facilitated by their use of [[organometallic chemistry|organometallic]] iron-based bonds in their protein-rich [[cuticle]]s. Based on synthetic replicas, the presence of iron in these structures increased [[elastic modulus]] 770 times, [[tensile strength]] 58 times, and [[toughness]] 92 times. The amount of stress required to permanently damage them increased 76 times.<ref>{{Cite journal| first = K| last = Sanderson|title = Mussels' iron grip inspires strong and stretchy polymer| journal = Chemical & Engineering News|page=8|volume = 95| issue = 44| publisher = American Chemical Society| date = 2017| url=https://cen.acs.org/articles/95/i44/Mussels-iron-grip-inspires-strong-stretchy-polymer.html|access-date=2 November 2017| doi=10.1021/cen-09544-notw3}}</ref>

===Nutrition===
==== Diet====
Iron is pervasive, but particularly rich sources of dietary iron include [[red meat]], [[oyster]]s, [[bean]]s, [[poultry]], [[fish]], [[leaf vegetable]]s, [[watercress]], [[tofu]], and [[blackstrap molasses]].<ref name="lpi" /> [[Bread]] and [[breakfast cereal]]s are sometimes specifically fortified with iron.<ref name="lpi" /><ref>[https://www.eatwell.gov.uk/healthissues/irondeficiency/ Food Standards Agency – Eat well, be well – Iron deficiency] {{webarchive|url=https://web.archive.org/web/20060808184739/https://www.eatwell.gov.uk/healthissues/irondeficiency/ |date=8 August 2006 }}. Eatwell.gov.uk (5 March 2012). Retrieved on 27 June 2012.</ref>

Iron provided by [[dietary supplement]]s is often found as [[iron(II) fumarate]], although [[iron(II) sulfate]] is cheaper and is absorbed equally well.<ref name="Ullmann" /> Elemental iron, or reduced iron, despite being absorbed at only one-third to two-thirds the efficiency (relative to iron sulfate),<ref>{{cite journal|last1=Hoppe|first1=M.|last2=Hulthén|first2=L.|last3=Hallberg|first3=L.|title=The relative bioavailability in humans of elemental iron powders for use in food fortification|journal=European Journal of Nutrition|volume=45|issue=1|pages=37–44|date=2005|pmid=15864409|doi=10.1007/s00394-005-0560-0|s2cid=42983904}}</ref> is often added to foods such as breakfast cereals or enriched wheat flour. Iron is most available to the body when [[Chelation|chelated]] to amino acids<ref name="pmid11377130">{{Cite journal|title=Effectiveness of treatment of iron-deficiency anemia in infants and young children with ferrous bis-glycinate chelate |journal=Nutrition |volume=17 |issue=5 |pages=381–4 |date=2001 |pmid=11377130| doi = 10.1016/S0899-9007(01)00519-6 |last1=Pineda |first1=O. |last2=Ashmead |first2=H. D.}}</ref> and is also available for use as a common [[iron supplement]]. [[Glycine]], the least expensive amino acid, is most often used to produce iron glycinate supplements.<ref name="Ashmead">{{Cite book|last = Ashmead |first = H. DeWayne |date = 1989 |title = ''Conversations on Chelation and Mineral Nutrition'' |publisher = Keats Publishing |isbn = 0-87983-501-X}}</ref>

====Dietary recommendations====
The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for iron in 2001.<ref name="lpi" /> The current EAR for iron for women ages 14{{nbnd}}18 is 7.9 mg/day, 8.1 mg/day for ages 19{{nbnd}}50 and 5.0 mg/day thereafter (postmenopause). For men, the EAR is 6.0 mg/day for ages 19 and up. The RDA is 15.0 mg/day for women ages 15{{nbnd}}18, 18.0 mg/day for ages 19{{nbnd}}50 and 8.0 mg/day thereafter. For men, 8.0 mg/day for ages 19 and up. RDAs are higher than EARs so as to identify amounts that will cover people with higher-than-average requirements. RDA for pregnancy is 27 mg/day and, for lactation, 9 mg/day.<ref name="lpi" /> For children ages 1{{nbnd}}3 years 7 mg/day, 10 mg/day for ages 4–8 and 8 mg/day for ages 9{{nbnd}}13. As for safety, the IOM also sets [[Tolerable upper intake level]]s (ULs) for vitamins and minerals when evidence is sufficient. In the case of iron, the UL is set at 45 mg/day. Collectively the EARs, RDAs and ULs are referred to as [[Dietary Reference Intake]]s.<ref>{{cite book|chapter= Iron|chapter-url= https://www.nal.usda.gov/sites/default/files/fnic_uploads//290-393_150.pdf|title= Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Iron|publisher= National Academy Press|year= 2001|pages= 290–393|pmid= 25057538|isbn= 0-309-07279-4|author1= Institute of Medicine (US) Panel on Micronutrients|access-date= 9 March 2017|archive-date= 9 September 2017|archive-url= https://web.archive.org/web/20170909191057/https://www.nal.usda.gov/sites/default/files/fnic_uploads//290-393_150.pdf|url-status= dead}}</ref>

The [[European Food Safety Authority]] (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the [[United States]]. For women the PRI is 13 mg/day ages 15{{nbnd}}17 years, 16 mg/day for women ages 18 and up who are premenopausal and 11 mg/day postmenopausal. For pregnancy and lactation, 16 mg/day. For men the PRI is 11 mg/day ages 15 and older. For children ages 1 to 14, the PRI increases from 7 to 11 mg/day. The PRIs are higher than the U.S. RDAs, with the exception of pregnancy.<ref>{{cite web | title = Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies| year = 2017| url = https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf|work=European Food Safety Authority}}</ref> The EFSA reviewed the same safety question did not establish a UL.<ref>{{cite web| title = Tolerable Upper Intake Levels For Vitamins And Minerals| publisher = European Food Safety Authority| year = 2006| url = https://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf}}</ref>

Infants may require iron supplements if they are bottle-fed cow's milk.<ref>{{cite web |url=https://bodyandhealth.canada.com/condition_info_details.asp?disease_id=274 |title=Iron Deficiency Anemia |publisher=MediResource |access-date=17 December 2008 |archive-date=16 December 2008 |archive-url=https://web.archive.org/web/20081216132821/http://bodyandhealth.canada.com/condition_info_details.asp?disease_id=274 |url-status=dead }}</ref> Frequent [[Blood donation|blood donors]] are at risk of low iron levels and are often advised to supplement their iron intake.<ref>{{Cite journal| doi= 10.1016/0925-5710(95)00426-2|pmid= 8867722|date= 1996|last1= Milman|first1=N.|title= Serum ferritin in Danes: studies of iron status from infancy to old age, during blood donation and pregnancy|volume= 63|issue= 2|pages= 103–35|journal= [[International Journal of Hematology]]|doi-access= free}}</ref>

For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For iron labeling purposes, 100% of the Daily Value was 18 mg, and {{as of|2016|May|27|lc=y|df=US}} remained unchanged at 18 mg.<ref name="FedReg">{{Cite web|url=https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf|title=Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels. FR page 33982.}}</ref><ref>{{cite web | title=Daily Value Reference of the Dietary Supplement Label Database (DSLD) | website=Dietary Supplement Label Database (DSLD) | url=https://www.dsld.nlm.nih.gov/dsld/dailyvalue.jsp | access-date=16 May 2020 | archive-date=7 April 2020 | archive-url=https://web.archive.org/web/20200407073956/https://dsld.nlm.nih.gov/dsld/dailyvalue.jsp | url-status=dead }}</ref> A table of the old and new adult daily values is provided at [[Reference Daily Intake]].

===Deficiency===
{{Main|Iron deficiency}}

Iron deficiency is the most common [[nutritional deficiency]] in the world.<ref name="lpi" /><ref>{{cite journal |author=Centers for Disease Control and Prevention |title=Iron deficiency – United States, 1999–2000 |journal=MMWR |date=2002 |volume=51 |issue=40 |pages=897–99 |url=https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5140a1.htm|pmid=12418542}}</ref><ref>{{cite book|first1=Robert C. |last1=Hider |first2=Xiaole|last2=Kong |editor=Astrid Sigel, Helmut Sigel and Roland K.O. Sigel |title=Interrelations between Essential Metal Ions and Human Diseases|series=Metal Ions in Life Sciences|volume=13 |year=2013|publisher=Springer|pages=229–94 |chapter=Chapter 8. Iron: Effect of Overload and Deficiency|doi=10.1007/978-94-007-7500-8_8|pmid=24470094|isbn=978-94-007-7499-5 }}</ref><ref>{{cite book |last1=Dlouhy |first1=Adrienne C. |last2=Outten |first2=Caryn E. |chapter=The Iron Metallome in Eukaryotic Organisms |editor1-first=Lucia|editor1-last=Banci |series=Metal Ions in Life Sciences |volume=12 |title=Metallomics and the Cell |year=2013 |pages=241–78 |publisher=Springer |isbn=978-94-007-5560-4 |doi=10.1007/978-94-007-5561-1_8|pmid=23595675 |pmc=3924584 }} electronic-book {{ISBN|978-94-007-5561-1}}</ref> When loss of iron is not adequately compensated by adequate dietary iron intake, a state of [[latent iron deficiency]] occurs, which over time leads to [[iron-deficiency anemia]] if left untreated, which is characterised by an insufficient number of red blood cells and an insufficient amount of hemoglobin.<ref>{{cite journal |author=CDC Centers for Disease Control and Prevention |title=Recommendations to Prevent and Control Iron Deficiency in the United States |journal=Morbidity and Mortality Weekly Report |date=3 April 1998 |volume=47 |issue=RR3 |page=1 |url=https://www.cdc.gov/mmwr/preview/mmwrhtml/00051880.htm |access-date=12 August 2014}}</ref> Children, [[pre-menopausal]] women (women of child-bearing age), and people with poor diet are most susceptible to the disease. Most cases of iron-deficiency anemia are mild, but if not treated can cause problems like fast or irregular heartbeat, complications during pregnancy, and delayed growth in infants and children.<ref>{{cite web|author=Centers for Disease Control and Prevention|title=Iron and Iron Deficiency |url=https://www.cdc.gov/nutrition/everyone/basics/vitamins/iron.html|access-date=12 August 2014}}</ref>

The brain is resistant to acute iron deficiency due to the slow transport of iron through the blood brain barrier.<ref>{{Cite journal |last1=Youdim |first1=M. B. |last2=Ben-Shachar |first2=D. |last3=Yehuda |first3=S. |date=September 1989 |title=Putative biological mechanisms of the effect of iron deficiency on brain biochemistry and behavior |journal=The American Journal of Clinical Nutrition |volume=50 |issue=3 Suppl |pages=607–615; discussion 615–617 |doi=10.1093/ajcn/50.3.607 |issn=0002-9165 |pmid=2773840|doi-access=free }}</ref> Acute fluctuations in iron status (marked by serum ferritin levels) do not reflect brain iron status, but prolonged nutritional iron deficiency is suspected to reduce brain iron concentrations over time.<ref>{{Cite journal |last1=Erikson |first1=K. M. |last2=Pinero |first2=D. J. |last3=Connor |first3=J. R. |last4=Beard |first4=J. L. |date=October 1997 |title=Regional brain iron, ferritin and transferrin concentrations during iron deficiency and iron repletion in developing rats |journal=The Journal of Nutrition |volume=127 |issue=10 |pages=2030–2038 |doi=10.1093/jn/127.10.2030 |issn=0022-3166 |pmid=9311961|doi-access=free }}</ref><ref>{{Cite journal |last1=Unger |first1=Erica L. |last2=Bianco |first2=Laura E. |last3=Jones |first3=Byron C. |last4=Allen |first4=Richard P. |last5=Earley |first5=Christopher J. |date=November 2014 |title=Low brain iron effects and reversibility on striatal dopamine dynamics |journal=Experimental Neurology |language=en |volume=261 |pages=462–468 |doi=10.1016/j.expneurol.2014.06.023 |pmc=4318655 |pmid=24999026}}</ref> In the brain, iron plays a role in oxygen transport, myelin synthesis, mitochondrial respiration, and as a cofactor for neurotransmitter synthesis and metabolism.<ref>{{Cite journal |last1=Ward |first1=Roberta J. |last2=Zucca |first2=Fabio A. |last3=Duyn |first3=Jeff H. |last4=Crichton |first4=Robert R. |last5=Zecca |first5=Luigi |date=October 2014 |title=The role of iron in brain ageing and neurodegenerative disorders |journal=The Lancet. Neurology |volume=13 |issue=10 |pages=1045–1060 |doi=10.1016/S1474-4422(14)70117-6 |issn=1474-4465 |pmc=5672917 |pmid=25231526}}</ref> Animal models of nutritional iron deficiency report biomolecular changes resembling those seen in Parkinson's and Huntington's disease.<ref>{{Cite journal |last1=Pino |first1=Jessica M. V. |last2=da Luz |first2=Marcio H. M. |last3=Antunes |first3=Hanna K. M. |last4=Giampá |first4=Sara Q. de Campos |last5=Martins |first5=Vilma R. |last6=Lee |first6=Kil S. |date=2017-05-17 |title=Iron-Restricted Diet Affects Brain Ferritin Levels, Dopamine Metabolism and Cellular Prion Protein in a Region-Specific Manner |journal=Frontiers in Molecular Neuroscience |volume=10 |pages=145 |doi=10.3389/fnmol.2017.00145 |issn=1662-5099 |pmc=5434142 |pmid=28567002 |doi-access=free }}</ref><ref>{{Cite journal |last1=Beard |first1=John |last2=Erikson |first2=Keith M. |last3=Jones |first3=Byron C. |date=2003-04-01 |title=Neonatal Iron Deficiency Results in Irreversible Changes in Dopamine Function in Rats |journal=The Journal of Nutrition |language=en |volume=133 |issue=4 |pages=1174–1179 |doi=10.1093/jn/133.4.1174 |pmid=12672939 |issn=0022-3166|doi-access=free }}</ref> However, age-related accumulation of iron in the brain has also been linked to the development of Parkinson's.<ref>{{cite journal |author1=Dominic J. Hare |author2=Kay L. Double |title=Iron and dopamine: a toxic couple |journal=Brain |volume=139 |issue=4 |date=April 2016 |pages=1026–1035 |doi=10.1093/brain/aww022|pmid=26962053 |doi-access=free }}</ref>

===Excess===
{{Main|Iron overload}}
[[Human iron metabolism|Iron uptake]] is tightly regulated by the human body, which has no regulated physiological means of excreting iron. Only small amounts of iron are lost daily due to mucosal and skin epithelial cell sloughing, so control of iron levels is primarily accomplished by regulating uptake.<ref>{{cite book|author1=Ramzi S. Cotran|author2=Vinay Kumar|author3=Tucker Collins|author4=Stanley Leonard Robbins|title=Robbins pathologic basis of disease|url={{Google books|kdhrAAAAMAAJ|keywords=|text=|plainurl=yes}}|access-date= 27 June 2012|date=1999|publisher=Saunders|isbn=978-0-7216-7335-6}}</ref> Regulation of iron uptake is impaired in some people as a result of a [[Genetic disorder|genetic defect]] that maps to the HLA-H gene region on [[chromosome 6]] and leads to abnormally low levels of [[hepcidin]], a key regulator of the entry of iron into the circulatory system in mammals.<ref name="pmid12663437">{{cite journal|author=Ganz T|title=Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation|journal=Blood|volume=102|issue=3|pages=783–8|date=August 2003|pmid=12663437|doi=10.1182/blood-2003-03-0672|s2cid=28909635|doi-access=free}}</ref> In these people, excessive iron intake can result in [[iron overload disorder]]s, known medically as [[hemochromatosis]].<ref name="lpi" /> Many people have an undiagnosed genetic susceptibility to iron overload, and are not aware of a family history of the problem. For this reason, people should not take iron supplements unless they suffer from [[iron deficiency (medicine)|iron deficiency]] and have consulted a doctor. Hemochromatosis is estimated to be the cause of 0.3–0.8% of all metabolic diseases of Caucasians.<ref>{{Cite journal|title=Hereditary hemochromatosis|journal=Rev Méd Interne|date=2000 |volume=21 |issue=11 |pages=961–71 |doi=10.1016/S0248-8663(00)00252-6 |pmid=11109593|last1=Durupt|first1=S.|last2=Durieu|first2=I.|last3=Nové-Josserand|first3=R.|last4=Bencharif|first4=L.|last5=Rousset|first5=H.|last6=Vital Durand|first6=D.}}</ref> <!--f[[MRI]] studies show that iron accumulates in the [[hippocampus]] of the brains of those with [[Alzheimer's disease]] and in the [[substantia nigra]] of those with [[Parkinson disease]].<ref>{{Cite journal| url = https://archneur.highwire.org/cgi/content/abstract/66/3/371 |pmid= 19273756|doi = 10.1001/archneurol.2008.586|date = 2009|last1 = Brar|first1 = S.|last2 = Henderson|first2 = D.|last3 = Schenck|first3 = J.|last4 = Zimmerman|first4 = E.A.|title = Iron accumulation in the substantia nigra of patients with Alzheimer disease and parkinsonism|volume = 66|issue = 3|pages = 371–74|journal = Archives of Neurology}}</ref>-->

Overdoses of ingested iron can cause excessive levels of free iron in the blood. High blood levels of free ferrous iron react with [[peroxide]]s to produce highly reactive [[free radical]]s that can damage [[DNA]], [[proteins]], [[lipids]], and other cellular components. Iron toxicity occurs when the cell contains free iron, which generally occurs when iron levels exceed the availability of [[transferrin]] to bind the iron. Damage to the cells of the [[Human gastrointestinal tract|gastrointestinal tract]] can also prevent them from regulating iron absorption, leading to further increases in blood levels. Iron typically damages cells in the [[heart]], [[liver]] and elsewhere, causing adverse effects that include [[coma]], [[metabolic acidosis]], [[Shock (circulatory)|shock]], [[liver failure]], [[coagulopathy]], long-term organ damage, and even death.<ref name="Cheney" /> Humans experience iron toxicity when the iron exceeds 20 milligrams for every kilogram of body mass; 60 milligrams per kilogram is considered a [[lethal dose]].<ref name="emed-topic285">{{cite web|url=https://www.emedicine.com/emerg/topic285.htm|title=Toxicity, Iron
| publisher = Medscape|access-date=23 May 2010}}</ref> Overconsumption of iron, often the result of children eating large quantities of [[ferrous sulfate]] tablets intended for adult consumption, is one of the most common toxicological causes of death in children under six.<ref name="emed-topic285" /> The [[Dietary Reference Intake]] (DRI) sets the Tolerable Upper Intake Level (UL) for adults at 45 mg/day. For children under fourteen years old the UL is 40 mg/day.<ref name="IOM">{{citation|title=Dietary Reference Intakes (DRIs): Recommended Intakes for Individuals |publisher=Food and Nutrition Board, Institute of Medicine, National Academies |year=2004 |url=https://www.iom.edu/Global/News%20Announcements/~/media/Files/Activity%20Files/Nutrition/DRIs/DRI_Summary_Listing.pdf |access-date=2009-06-09 |url-status=dead |archive-url=https://web.archive.org/web/20130314000722/https://www.iom.edu/Global/News%20Announcements/~/media/Files/Activity%20Files/Nutrition/DRIs/DRI_Summary_Listing.pdf |archive-date=14 March 2013 }}</ref>

The medical management of iron toxicity is complicated, and can include use of a specific [[chelation|chelating]] agent called [[deferoxamine]] to bind and expel excess iron from the body.<ref name="Cheney">{{Cite journal| last1 =Cheney|first1 =K.| last2 =Gumbiner|first2 =C.| last3 = Benson|first3 =B.| last4 = Tenenbein|first4 =M.|title=Survival after a severe iron poisoning treated with intermittent infusions of deferoxamine |journal=J Toxicol Clin Toxicol |volume=33 |issue=1 |pages=61–66 |date=1995 |pmid=7837315 |doi=10.3109/15563659509020217}}</ref><ref>{{Cite journal| last = Tenenbein|first = M.|title=Benefits of parenteral deferoxamine for acute iron poisoning |journal=J Toxicol Clin Toxicol |volume=34 |issue=5 |pages=485–89 |date=1996 |pmid=8800185 |doi=10.3109/15563659609028005}}</ref><ref name="pmid21102602">{{cite journal |vauthors=Wu H, Wu T, Xu X, Wang J, Wang J | title = Iron toxicity in mice with collagenase-induced intracerebral hemorrhage | journal = J Cereb Blood Flow Metab | volume = 31 | issue = 5 | pages = 1243–50 |date=May 2011 | pmid = 21102602 | doi =10.1038/jcbfm.2010.209 | pmc=3099628}}</ref>

===ADHD===
Some research has suggested that low [[Thalamus|thalamic]] iron levels may play a role in the pathophysiology of [[Attention deficit hyperactivity disorder|ADHD]].<ref>{{cite journal |last1=Robberecht |first1=Harry |display-authors=etal |title=Magnesium, Iron, Zinc, Copper and Selenium Status in Attention-Deficit/Hyperactivity Disorder (ADHD) |journal=Molecules |year=2020 |volume=25 |issue=19 |page=4440 |doi=10.3390/molecules25194440 |pmid=32992575 |pmc=7583976|doi-access=free }}</ref> Some researchers have found that iron supplementation can be effective especially in the [[Attention deficit hyperactivity disorder predominantly inattentive|inattentive subtype]] of the disorder.<ref>{{cite journal |last1=Soto-Insuga |first1=V |display-authors=etal |title=[Role of iron in the treatment of attention deficit-hyperactivity disorder] |journal=An Pediatr (Barc) |date=2013 |volume=79 |issue=4 |pages=230–235 |doi=10.1016/j.anpedi.2013.02.008 |pmid=23582950}}</ref>

Some researchers in the 2000s suggested a link between low levels of iron in the blood and ADHD. A 2012 study found no such correlation.<ref>{{Cite journal |last1=Donfrancesco |first1=Renato |last2=Parisi |first2=Pasquale |last3=Vanacore |first3=Nicola |last4=Martines |first4=Francesca |last5=Sargentini |first5=Vittorio |last6=Cortese |first6=Samuele |date=May 2013 |title=Iron and ADHD: Time to Move Beyond Serum Ferritin Levels |journal=Journal of Attention Disorders |language=en |volume=17 |issue=4 |pages=347–357 |doi=10.1177/1087054711430712 |pmid=22290693 |s2cid=22445593 |issn=1087-0547}}</ref>

===Cancer===
The role of iron in cancer defense can be described as a "double-edged sword" because of its pervasive presence in non-pathological processes.<ref>{{cite book|last1=Thévenod|first1=Frank
|editor1-last=Sigel|editor1-first=Astrid|editor2-last=Sigel|editor2-first=Helmut|editor3-last=Freisinger|editor3-first=Eva|editor4-last=Sigel|editor4-first=Roland K. O.
|title=Metallo-Drugs: Development and Action of Anticancer Agents
|date=2018
|doi= 10.1515/9783110470734-021
|pmid=29394034
|publisher=de Gruyter GmbH
|location=Berlin
|chapter= Chapter 15. Iron and Its Role in Cancer Defense: A Double-Edged Sword
|series=Metal Ions in Life Sciences 18
|volume=18
|pages= 437–67}}
</ref> People having [[chemotherapy]] may develop iron deficiency and [[anemia]], for which [[Intravenous iron infusion|intravenous iron therapy]] is used to restore iron levels.<ref name="beguin">{{cite journal|pmid=24275533|year=2014|last1=Beguin|first1=Y|title=Epidemiological and nonclinical studies investigating effects of iron in carcinogenesis--a critical review|journal=Critical Reviews in Oncology/Hematology|volume=89|issue=1|pages=1–15|last2=Aapro|first2=M|last3=Ludwig|first3=H|last4=Mizzen|first4=L|last5=Osterborg|first5=A|doi=10.1016/j.critrevonc.2013.10.008|doi-access=free}}</ref> Iron overload, which may occur from high consumption of red meat,<ref name="lpi" /> may initiate [[tumor]] growth and increase susceptibility to cancer onset,<ref name="beguin" /> particularly for [[colorectal cancer]].<ref name="lpi" />
<!--===Bioremediation===

Iron-eating bacteria live in the hulls of [[sunken ship]]s such as the ''[[Titanic]]''.<ref>{{cite book
  | last = Ward
  | first = Greg
  | title = The Rough Guide to the ''Titanic''
  | date = 2012
  | publisher = Rough Guides Ltd
  | location = London
  | page=171
  | isbn = 978-1-4053-8699-9
  }}</ref> The acidophile bacteria ''[[Acidithiobacillus|Acidithiobacillus ferrooxidans]]'', ''[[Leptospirillum ferrooxidans]]'', ''[[Sulfolobus]]'' spp., ''[[Acidianus|Acidianus brierleyi]]'' and ''[[Sulfobacillus thermosulfidooxidans]]'' can oxidize ferrous iron enzymically.<ref>{{cite journal|url=https://mic.sgmjournals.org/content/156/3/609.full|title=Metals, minerals and microbes: geomicrobiology and bioremediation|journal=Microbiology|last=Gadd |first= Geoffrey Michael |volume=156|date=March 2010|pages=609–43|doi=10.1099/mic.0.037143-0|pmid=20019082|issue=3}}</ref> A sample of the fungus ''[[Aspergillus niger]]'' was found growing from gold mining solution, and was found to contain cyano metal complexes such as gold, silver, copper iron and zinc. The fungus also plays a role in the solubilization of heavy metal sulfides.<ref>{{cite book|url={{Google books|WY3YvfNoouMC|page=PA533|keywords=|text=|plainurl=yes}}|title=Mycoremediation: Fungal Bioremediation|last=Singh |first= Harbhajan |page=509}}</ref>-->

===Marine systems===
Iron plays an essential role in marine systems and can act as a limiting nutrient for planktonic activity.<ref>{{cite journal | last1 = Morel | first1 = F.M.M. | last2 = Hudson | first2 = R.J.M. | last3 = Price | first3 = N.M. | year = 1991 | title = Limitation of productivity by trace metals in the sea | url = | journal = Limnology and Oceanography | volume = 36 | issue = 8| pages = 1742–1755 | doi = 10.4319/lo.1991.36.8.1742 | bibcode = 1991LimOc..36.1742M }}</ref> Because of this, too much of a decrease in iron may lead to a decrease in growth rates in phytoplanktonic organisms such as diatoms.<ref>{{cite journal | last1 = Brezezinski | first1 = M.A. | last2 = Baines | first2 = S.B. | last3 = Balch | first3 = W.M. | last4 = Beucher | first4 = C.P. | last5 = Chai | first5 = F. | last6 = Dugdale | first6 = R.C. | last7 = Krause | first7 = J.W. | last8 = Landry | first8 = M.R. | last9 = Marchi | first9 = A. | last10 = Measures | first10 = C.I. | last11 = Nelson | first11 = D.M. | last12 = Parker | first12 = A.E. | last13 = Poulton | first13 = A.J. | last14 = Selph | first14 = K.E. | last15 = Strutton | first15 = P.G. | last16 = Taylor | first16 = A.G. | last17 = Twining | first17 = B.S. | year = 2011 | title = Co-limitation of diatoms by iron and silicic acid in the equatorial Pacific | url = | journal = Deep-Sea Research Part II: Topical Studies in Oceanography | volume = 58 | issue = 3–4| pages = 493–511 | doi = 10.1016/j.dsr2.2010.08.005 | bibcode = 2011DSRII..58..493B }}</ref> Iron can also be oxidized by marine microbes under conditions that are high in iron and low in oxygen.<ref>{{cite journal | last1 = Field | first1 = E. K. | last2 = Kato | first2 = S. | last3 = Findlay | first3 = A. J. | last4 = MacDonald | first4 = D. J. | last5 = Chiu | first5 = B. K. | last6 = Luther | first6 = G. W. | last7 = Chan | first7 = C. S. | year = 2016 | title = Planktonic marine iron oxidizers drive iron mineralization under low-oxygen conditions | url = | journal = Geobiology | volume = 14 | issue = 5| pages = 499–508 | doi = 10.1111/gbi.12189 | pmid = 27384464 | bibcode = 2016Gbio...14..499F }}</ref>

Iron can enter marine systems through adjoining rivers and directly from the atmosphere. Once iron enters the ocean, it can be distributed throughout the water column through ocean mixing and through recycling on the cellular level.<ref>{{cite journal | last1 = Wells | first1 = M.L. | last2 = Price | first2 = N.M. | last3 = Bruland | first3 = K.W. | year = 1995 | title = Iron chemistry in seawater and its relationship to phytoplankton: a workshop report | url = | journal = Marine Chemistry | volume = 48 | issue = 2| pages = 157–182 | doi = 10.1016/0304-4203(94)00055-I | bibcode = 1995MarCh..48..157W }}</ref> In the arctic, sea ice plays a major role in the store and distribution of iron in the ocean, depleting oceanic iron as it freezes in the winter and releasing it back into the water when thawing occurs in the summer.<ref>{{cite journal | last1 = Lannuzel | first1 = D. | last2 = Vancoppenolle | first2 = M. | last3 = van der Merwe | first3 = P. | last4 = de Jong | first4 = J. | last5 = Meiners | first5 = K.M. | last6 = Grotti | first6 = M. | last7 = Nishioska | first7 = J. | last8 = Schoemann | year = 2016 | title = Iron in sea ice: Review and new insights | url = | journal = Elementa: Science of the Anthropocene | volume = 4 | issue = | page = 000130 | doi = 10.12952/journal.elementa.000130 | bibcode = 2016EleSA...4.0130L }}</ref> The iron cycle can fluctuate the forms of iron from aqueous to particle forms altering the availability of iron to primary producers.<ref>{{cite journal | last1 = Raiswell | first1 = R | year = 2011 | title = Iron Transport from the Continents to the Open Ocean: The Aging–Rejuvenation Cycle | url = | journal = Elements | volume = 7 | issue = 2| pages = 101–106 | doi = 10.2113/gselements.7.2.101 | bibcode = 2011Eleme...7..101R }}</ref> Increased light and warmth increases the amount of iron that is in forms that are usable by primary producers.<ref>{{cite journal | last1 = Tagliabue | first1 = A. | last2 = Bopp | first2 = L. | last3 = Aumont | first3 = O. | last4 = Arrigo | first4 = K.R. | year = 2009 | title = Influence of light and temperature on the marine iron cycle: From theoretical to global modeling | url = https://hal.science/hal-00413634/file/2008GB003214.pdf| journal = Global Biogeochemical Cycles | volume =  23| issue = 2| page =  | doi = 10.1029/2008GB003214 | bibcode = 2009GBioC..23.2017T }}</ref>