Most cell types take up iron primarily through  receptor-mediated endocytosis  via  transferrin receptor 1  (TFR1),  transferrin receptor 2  (TFR2) and  GAPDH . TFR1 has a 30-fold higher affinity for transferrin-bound iron than TFR2 and thus is the main player in this process. [ 34 ] [ 35 ]  The higher order multifunctional glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) also acts as a transferrin receptor. [ 36 ] [ 37 ]  Transferrin-bound ferric iron is recognized by these transferrin receptors, triggering a conformational change that causes endocytosis. Iron then enters the cytoplasm from the endosome via importer DMT1 after being reduced to its ferrous state by a STEAP family reductase. [ 38 ]


Alternatively, iron can enter the cell directly via plasma membrane divalent cation importers such as DMT1 and ZIP14 (Zrt-Irt-like protein 14). [ 39 ]  Again, iron enters the cytoplasm in the ferrous state after being reduced in the extracellular space by a reductase such as STEAP2, STEAP3 (in red blood cells), Dcytb (in enterocytes) and SDR2. [ 38 ]


In the cytoplasm, ferrous iron is found in a soluble, chelatable state which constitutes the labile iron pool (~0.001 mM). [ 40 ]  In this pool, iron is thought to be bound to low-mass compounds such as peptides, carboxylates and phosphates, although some might be in a free, hydrated form ( aqua ions ). [ 40 ]  Alternatively, iron ions might be bound to specialized proteins known as  metallochaperones . [ 41 ]  Specifically, poly-r(C)-binding proteins  PCBP1  and  PCBP2  appear to mediate transfer of free iron to ferritin (for storage) and  non-heme iron enzymes  (for use in catalysis). [ 39 ] [ 42 ]  The labile iron pool is potentially toxic due to iron's ability to generate reactive oxygen species. Iron from this pool can be taken up by mitochondria via  mitoferrin  to synthesize Fe-S clusters and heme groups. [ 38 ]


Iron can be stored in ferritin as ferric iron due to the  ferroxidase  activity of the ferritin heavy chain. [ 43 ]  Dysfunctional ferritin may accumulate as  hemosiderin , which can be problematic in cases of iron overload. [ 44 ]  The ferritin storage iron pool is much larger than the labile iron pool, ranging in concentration from 0.7 mM to 3.6 mM. [ 40 ]


Iron export occurs in a variety of cell types, including  neurons , red blood cells, macrophages and enterocytes. The latter two are especially important since systemic iron levels depend upon them. There is only one known iron exporter,  ferroportin . [ 45 ]  It transports ferrous iron out of the cell, generally aided by  ceruloplasmin  and/or  hephaestin  (mostly in enterocytes), which oxidize iron to its ferric state so it can bind ferritin in the extracellular medium. [ 38 ]   Hepcidin  causes the internalization of ferroportin, decreasing iron export. Besides, hepcidin seems to downregulate both TFR1 and DMT1 through an unknown mechanism. [ 46 ]  Another player assisting ferroportin in effecting cellular iron export is GAPDH. [ 47 ]  A specific post translationally modified isoform of GAPDH is recruited to the surface of iron loaded cells where it recruits apo-transferrin in close proximity to ferroportin so as to rapidly chelate the iron extruded. [ 48 ]


The expression of hepcidin, which only occurs in certain cell types such as  hepatocytes , is tightly controlled at the transcriptional level and it represents the link between cellular and systemic iron homeostasis due to hepcidin's role as "gatekeeper" of iron release from enterocytes into the rest of the body. [ 38 ]   Erythroblasts  produce  erythroferrone , a hormone which inhibits hepcidin and so increases the availability of iron needed for hemoglobin synthesis. [ 49 ]


Although some control exists at the transcriptional level, the regulation of cellular iron levels is ultimately controlled at the translational level by  iron-responsive element-binding proteins  IRP1 and especially IRP2. [ 50 ]  When iron levels are low, these proteins are able to bind to  iron-responsive elements  (IREs). IREs are stem loop structures in the untranslated regions (UTRs) of mRNA. [ 38 ]


Both ferritin and ferroportin contain an IRE in their 5' UTRs, so that under iron deficiency their translation is repressed by IRP2, preventing the unnecessary synthesis of storage protein and the detrimental export of iron. In contrast, TFR1 and some DMT1 variants contain 3' UTR IREs, which bind IRP2 under iron deficiency, stabilizing the mRNA, which guarantees the synthesis of iron importers. [ 38 ]


Iron plays an essential role in marine systems and can act as a limiting nutrient for planktonic activity. [ 51 ]  Because of this, too much of a decrease in iron may lead to a decrease in growth rates in phytoplanktonic organisms such as diatoms. [ 52 ]  Iron can also be oxidized by marine microbes under conditions that are high in iron and low in oxygen. [ 53 ]


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. [ 54 ]  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. [ 55 ]  The iron cycle can fluctuate the forms of iron from aqueous to particle forms altering the availability of iron to primary producers. [ 56 ]  Increased light and warmth increases the amount of iron that is in forms that are usable by primary producers. [ 57 ]


Landsupport  (spelling: LANDSUPPORT) is a pilot consulting project funded by the  European Union  for land use for the near-natural modeling of different types and methods of land use while at the same time protecting the environment. [ 1 ] [ 2 ]


In the long term, sustainable use of the soil must be guaranteed in order to meet the needs of the world's population. The project brings together numerous universities, research institutions, companies and stakeholders with the aim of creating a web-based, free system to support practical agriculture and land users in making decisions about sustainable land use, environmental protection and agricultural use.


With the active participation of various and numerous stakeholders in and outside Europe, the consortium also aims at legislation at European level, based on scientific data that is processed and modeled in the system.


In the research framework program Horizon 2020, the project is organized under the direction of  Fabio Terribile  at the  University of Naples Federico II .


The Landsupport consortium consists of the following partners:


The results of the investigations are internationally evaluated by the members in specialist committees and made available to practice and the responsible bodies at regional and state level, as well as to the European Uninion for  legislative and approval procedures.


Certain  lithium compounds , also known as  lithium salts , are used as  psychiatric medication , [ 5 ]  primarily for  bipolar disorder  and for  major depressive disorder . [ 5 ]  Lithium is taken orally (by mouth). [ 5 ]


Common side effects include  increased urination , shakiness of the hands, and increased thirst. [ 5 ]  Serious side effects include  hypothyroidism ,  diabetes insipidus , and  lithium toxicity . [ 5 ]  Blood level monitoring is recommended to decrease the risk of potential toxicity. [ 5 ]  If levels become too high, diarrhea, vomiting, poor coordination, sleepiness, and  ringing in the ears  may occur. [ 5 ]  Lithium is  teratogenic  and can cause birth defects at high doses, especially during the first trimester of pregnancy. The use of lithium while breastfeeding is controversial; however, many international health authorities advise against it, and the long-term outcomes of perinatal lithium exposure have not been studied. [ 6 ]  The  American Academy of Pediatrics  lists lithium as contraindicated for pregnancy and lactation. [ 7 ]  The United States  Food and Drug Administration  categorizes lithium as having positive evidence of risk for pregnancy and possible hazardous risk for lactation. [ 7 ] [ 8 ]


Lithium salts are classified as  mood stabilizers . [ 5 ]  Lithium's mechanism of action is not known. [ 5 ]


In the nineteenth century, lithium was used in people who had  gout ,  epilepsy , and  cancer . [ 9 ]  Its use in the treatment of  mental disorders  began with  Carl Lange  in Denmark [ 10 ]  and  William Alexander Hammond  in New York City, [ 11 ]  who used lithium to treat  mania  from the 1870s onwards, based on now-discredited theories involving its effect on uric acid. Use of lithium for mental disorders was re-established (on a different theoretical basis) in 1948 by  John Cade  in Australia. [ 9 ]   Lithium carbonate  is on the  World Health Organization's List of Essential Medicines , [ 12 ]  and is available as a  generic medication . [ 5 ]  In 2022, it was the 212th most commonly prescribed medication in the United States, with more than 1   million prescriptions. [ 13 ] [ 14 ]  It appears to be underused in older people, [ 15 ]  and in certain countries, for reasons including patients’ negative beliefs about lithium. [ 16 ]


In 1970, lithium was approved by the United States  Food and Drug Administration  (FDA) for the treatment of bipolar disorder, which remains its primary use in the US. [ 5 ] [ 17 ]  It is sometimes used when other treatments are not effective in a number of other conditions, including  major depression , [ 18 ]   schizophrenia , disorders of impulse control, and some psychiatric disorders in children. [ 5 ]  Because the FDA has not approved lithium for the treatment of other disorders, such use is  off-label . [ 19 ] [ 18 ]


Lithium is primarily used as a maintenance drug in the treatment of bipolar disorder to stabilize mood and prevent  manic episodes , but it may also be helpful in the acute treatment of manic episodes. [ 20 ]  Although recommended by treatment guidelines for the treatment of depression in bipolar disorder, the evidence that lithium is superior to placebo for acute depression is low-quality; [ 21 ] [ 22 ]   atypical antipsychotics  are considered more effective for treating acute depressive episodes. [ 23 ]   Lithium carbonate  treatment was previously considered to be unsuitable for children; however, more recent studies show its effectiveness for treatment of early-onset bipolar disorder in children as young as eight. The required dosage is slightly less than the toxic level (representing a low  therapeutic index ), requiring close monitoring of blood levels of lithium carbonate during treatment. [ 24 ]  Within the therapeutic range there is a dose-response relationship. [ 25 ]  A limited amount of evidence suggests lithium carbonate may contribute to the treatment of substance use disorders for some people with bipolar disorder. [ 26 ] [ 27 ] [ 28 ]  Although it is believed that lithium prevents suicide in people with bipolar disorder, a 2022 systematic review found that "Evidence from randomised trials is inconclusive and does not support the idea that lithium prevents suicide or suicidal behaviour." [ 29 ]


Lithium is recommended for the treatment of schizophrenic disorders only after other antipsychotics have failed; it has limited effectiveness when used alone. [ 5 ]  The results of different clinical studies of the efficacy of combining lithium with antipsychotic therapy for treating schizophrenic disorders have varied. [ 5 ]


Lithium is widely prescribed as an adjunct treatment for depression. [ 19 ]


If therapy with antidepressants (such as  selective serotonin reuptake inhibitors  [SSRIs]) does not fully treat and discontinue [ 30 ]  the symptoms of  major depressive disorder  (MDD) (also known as refractory depression or treatment resistant depression [TRD]) [ 31 ]  then a second  augmentation agent  is sometimes added to the therapy. [ 32 ]  Lithium is one of the few augmentation agents for antidepressants to demonstrate efficacy in treating MDD in multiple randomized controlled trials and it has been prescribed ( off-label ) for this purpose since the 1980s. [ 18 ]  A 2019 systematic review found some evidence of the clinical utility of adjunctive lithium, but the majority of supportive evidence is dated. [ 33 ]


While  SSRIs  have been mentioned above as a drug class in which lithium is used to augment, there are other classes in which lithium is added to increase effectiveness. Such classes are  antipsychotics  (used for bipolar disorder) as well as  antiepileptic  drugs (used for both psychiatric and epileptic cases).  Lamotrigine  and  topiramate  are two specific antiepileptic drugs in which lithium is used to augment. [ 34 ]


There are a few old studies indicating efficacy of lithium for acute depression with lithium having the same efficacy as  tricyclic antidepressants . [ 35 ]  A recent study concluded that lithium works best on chronic and recurrent depression when compared to modern antidepressant (i.e. citalopram) but not for patients with no history of depression. [ 36 ]  A 2019 systemic review found no evidence to support the use of lithium for monotherapy. [ 33 ]


Lithium is widely believed to prevent suicide and is often used in clinical practice towards that end. However, meta-analyses, faced with evidence base limitations, have yielded differing results, and it therefore remains unclear whether or not lithium is efficacious in the prevention of suicide. [ 37 ] [ 38 ] [ 39 ] [ 40 ] [ 41 ] [ 42 ]  However, some evidence suggets it is effective in significantly reducing the risk of  self-harm  and  unintentional injury  for bipolar disorder in comparison to no treatment and to  anti-psychotics  or  valporate . [ 43 ] [ 44 ]  According to meta-analyses, the increased presence of lithium in drinking water is correlated with lower overall suicide rates, especially among men. It is noted that further testing is needed to confirm this benefit. [ 45 ] [ 46 ]


Alzheimer's disease affects forty-five million people and is the fifth leading cause of death in the 65-plus population. [ 47 ] [ failed verification ]  There is no complete cure for the disease, currently. However, lithium is being evaluated for its effectiveness as a potential therapeutic measure. One of the leading causes of Alzheimer's is the hyperphosphorylation of the tau protein by the enzyme GSK-3, which leads to the overproduction of amyloid peptides that cause cell death. [ 47 ]  To combat this toxic amyloid aggregation, lithium upregulates the production of neuroprotectors and neurotrophic factors, as well as inhibiting the GSK-3 enzyme. [ 48 ]  Lithium also stimulates neurogenesis within the hippocampus, making it thicker. [ 48 ]  Yet another cause of Alzheimer's disease is the dysregulation of calcium ions within the brain. [ 49 ]  Too much or too little calcium within the brain can lead to cell death. [ 49 ]  Lithium can restore intracellular calcium homeostasis by inhibiting the wrongful influx of calcium upstream. [ 49 ]  It also promotes the redirection of the influx of calcium ions into the lumen of the endoplasmic reticulum of the cells to reduce the oxidative stress within the mitochondria. [ 49 ]


In 2009, a study was performed by Hampel and colleagues [ 50 ]  that asked patients with Alzheimer's to take a low dose of lithium daily for three months; it resulted in a significant slowing of cognitive decline, benefitting patients being in the prodromal stage the most. [ 48 ]  Upon a secondary analysis, the brains of the Alzheimer's patients were studied and shown to have an increase in BDNF markers, meaning they had actually shown cognitive improvement. [ 48 ]  Another study, a population study this time by Kessing et al., [ 51 ]  showed a negative correlation between Alzheimer's disease deaths and the presence of lithium in drinking water. [ 48 ]  Areas with increased lithium in their drinking water showed less dementia overall in their population. [ 48 ]


Those who use lithium should receive regular serum level tests and should monitor thyroid and kidney function for abnormalities, as it interferes with the regulation of  sodium  and water levels in the body, and can cause  dehydration . Dehydration, which is compounded by heat, can result in increasing lithium levels. The dehydration is due to lithium inhibition of the action of  antidiuretic hormone , which normally enables the kidney to reabsorb water from urine. This causes an inability to concentrate urine, leading to consequent loss of body water and thirst. [ 52 ]


Lithium concentrations in whole blood, plasma, serum, or urine may be measured using instrumental techniques as a guide to therapy, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdosage. Serum lithium concentrations are usually in the range of 0.5–1.3  mmol/L  (0.5–1.3  mEq/L ) in well-controlled people, but may increase to 1.8–2.5 mmol/L in those who accumulate the drug over time and to 3–10 mmol/L in acute overdose. [ 53 ] [ 54 ]


Lithium salts have a narrow therapeutic/toxic ratio, so should not be prescribed unless facilities for monitoring  plasma  concentrations are available. Doses are adjusted to achieve plasma concentrations of 0.4 [ a ] [ b ]  to 1.2 mmol/L [ 55 ]  on samples taken 12 hours after the preceding dose.


Given the rates of thyroid dysfunction, thyroid parameters should be checked before lithium is instituted and monitored after 3–6 months and then every 6–12 months. [ 56 ]


Given the risks of kidney malfunction, serum creatinine, and eGFR should be checked before lithium is instituted and monitored after 3–6 months at regular intervals. Patients who have a rise in creatinine on three or more occasions, even if their eGFR is > 60 ml/min/
1.73m2 require further evaluation, including a urinalysis for haematuria, and proteinuria, a review of their medical history with attention paid to cardiovascular, urological, and medication history, and blood pressure control and management. Overt proteinuria should be further quantified with a urine protein-to-creatinine ratio. [ 57 ]


For patients who have achieved long-term remission, it is recommended to discontinue lithium gradually and in a controlled fashion. [ 58 ] [ 35 ]


Discontinuation symptoms may occur in patients stopping the medication including irritability, restlessness, and somatic symptoms like vertigo, dizziness, or lightheadedness. Symptoms occur within the first week and are generally mild and self-limiting within weeks. [ 59 ]


Studies testing  prophylactic  use of lithium in cluster headaches (when compared to  verapamil ),  migraine  attacks, and  hypnic headache  indicate good efficacy. [ 35 ]


The adverse effects of lithium include: [ 60 ] [ 61 ] [ 62 ] [ 63 ] [ 64 ] [ 65 ] [ 66 ]


Lithium carbonate can induce a 1–2 kg of weight gain. [ 72 ]


In addition to tremors, lithium treatment appears to be a risk factor for development of  parkinsonism -like symptoms, although the causal mechanism remains unknown. [ 73 ]


In the average bipolar patient, chronic lithium use is not associated with cognitive decline. [ 74 ]


Most side effects of lithium are dose-dependent. The lowest effective dose is used to limit the risk of side effects.


The rate of  hypothyroidism  is around six times higher in people who take lithium. Low thyroid hormone levels in turn increase the likelihood of developing depression. People taking lithium thus should routinely be assessed for hypothyroidism and treated with synthetic thyroxine if necessary. [ 72 ]


Because lithium competes with the  antidiuretic hormone  in the kidney, it increases water output into the urine, a condition called nephrogenic  diabetes insipidus . Clearance of lithium by the kidneys is usually successful with certain diuretic medications, including  amiloride  and  triamterene . [ 75 ]  It increases the appetite and thirst ("polydypsia") and reduces the activity of  thyroid hormone  ( hypothyroidism ). [ 76 ] [ 77 ]  The latter can be corrected by treatment with  thyroxine  and does not require the lithium dose to be adjusted. Lithium is also believed to cause renal dysfunction, although this does not appear to be common. [ 78 ]


Lambert et al. (2016), comparing the rate of hypothyroidism in patients with bipolar disorder treated with 9 different medications, found that lithium users do not have a particularly high rate of hypothyroidism (8.8%) among BD patients – only 1.39 times the rate in  oxcarbazepine  users (6.3%). Lithium and quetiapine are not statistically different in terms of hypothyroidism rates. However, lithium users are tested much more frequently for hypothyroidism than those using other drugs. The authors write that there may be an element of surveillance bias in understanding lithium's effects on the thyroid glands, as lithium users are tested 2.3–3.1 times as often. Furthermore, the authors argue that because hypothyroidism is common among BD patients regardless of lithium treatment, regular thyroid testing should be applied to all BD patients, not just those on lithium. [ 79 ] [ 70 ]


Lithium is a  teratogen , which can cause birth defects in a small number of newborns.  Case reports  and several  retrospective studies  have demonstrated possible increases in the rate of a  congenital heart defects  including  Ebstein's anomaly  if taken during pregnancy. Teratogenicity is affected by trimester and dose of Lithium. Most significantly affecting first-trimester cardiac development with greater effects at higher doses.  [ 80 ] [ 81 ] [ 82 ]


As the risks of stopping Lithium can be significant, patients are sometimes recommended to stay on this medicine while pregnant. Careful weighing of the risks and benefits should be made in consultation with a  psychiatric physician .  [ 83 ]


For patients who are exposed to lithium, or plan to stay on the medication throughout their pregnancy, fetal  echocardiography  is routinely performed to monitor for cardiac anomalies. [ 84 ]


While lithium is typically the most effective treatment, possible alternatives to Lithium include  Lamotrigine  and  Second generation Antipsychotics  for the treatment of acute  bipolar depression  or for the management of bipolar patients with  normal mood  during pregnancy.


While only small amounts of Lithium are transmitted to the infant in breastmilk, there is limited data on the safety of  Breastfeeding  while on Lithium. Medical evaluation and monitoring of infants consuming breastmilk during maternal prescription may be indicated. [ 85 ] [ 86 ] [ 87 ]


Lithium has been associated with several forms of kidney injury. [ 88 ] [ 89 ]   It is estimated that impaired urinary concentrating ability is present in at least half of individuals on chronic lithium therapy, a condition called lithium-induced  nephrogenic diabetes insipidus . [ 89 ]  Continued use of lithium can lead to more serious  kidney damage  in an aggravated form of  diabetes insipidus . [ 90 ] [ 91 ]  In rare cases, some forms of lithium-caused kidney damage may be progressive and lead to end-stage kidney failure with a reported incidence of 0.2% to 0.7%. [ 92 ]


Some reports of kidney damage may be wrongly attributed to lithium, increasing the apparent rate of this adverse effect. [ 68 ]  Nielsen et al. (2018), citing 6 large observational studies since 2010, argue that findings of decreased kidney function are partially inflated by surveillance bias. Furthermore, modern data does not show that lithium increases the risk of end-stage kidney disease. [ 70 ]  Davis et al. (2018), using literature from a wider timespan (1977–2018), also found that lithium's association with chronic kidney disease is unproven with various contradicting results. They also find contradicting results regarding end-stage kidney disease. [ 93 ]


A 2015 nationwide study suggests that chronic kidney disease can be avoided by maintaining the serum lithium concentration at a level of 0.6–0.8 mmol/L and by monitoring  serum creatinine  every 3–6 months. [ 70 ]


Lithium-associated  hyperparathyroidism  is the leading cause of  hypercalcemia  in lithium-treated patients. Lithium may lead to exacerbation of pre-existing  primary hyperparathyroidism  or cause an increased set-point of calcium for parathyroid hormone suppression, leading to  parathyroid hyperplasia .


Lithium  plasma   concentrations  are known to be increased with concurrent use of  diuretics —especially  loop diuretics  (such as furosemide) and  thiazides —and  non-steroidal anti-inflammatory drugs  (NSAIDs) such as  ibuprofen . [ 60 ]  Lithium concentrations can also be increased with concurrent use of  ACE inhibitors  such as  captopril ,  enalapril , and  lisinopril . [ 94 ]


Lithium is primarily  cleared  from the body through  glomerular filtration , but some is then reabsorbed together with sodium through the  proximal tubule . Its levels are therefore sensitive to water and  electrolyte  balance. [ 95 ]  Diuretics act by lowering water and sodium levels; this causes more reabsorption of lithium in the proximal tubules so that the removal of lithium from the body is less, leading to increased blood levels of lithium. [ 95 ] [ 96 ]  ACE inhibitors have also been shown in a retrospective case-control study to increase lithium concentrations. This is likely due to constriction of the afferent arteriole of the glomerulus, resulting in decreased glomerular filtration rate and clearance. Another possible mechanism is that ACE inhibitors can lead to a decrease in sodium and water. This will increase lithium reabsorption and its concentrations in the body. [ 95 ]


Some drugs can increase the clearance of lithium from the body, which can result in decreased lithium levels in the blood. These drugs include  theophylline ,  caffeine , and  acetazolamide . Additionally, increasing dietary  sodium  intake may also reduce lithium levels by prompting the kidneys to excrete more lithium. [ 97 ]


Lithium is known to be a potential precipitant of  serotonin syndrome  in people concurrently on serotonergic medications such as  antidepressants ,  buspirone  and certain opioids such as  pethidine  (meperidine),  tramadol ,  oxycodone ,  fentanyl  and others. [ 60 ] [ 98 ]  Lithium co-treatment is also a risk factor for  neuroleptic malignant syndrome  in people on antipsychotics and other antidopaminergic medications. [ 99 ]


High doses of  haloperidol ,  fluphenazine , or  flupenthixol  may be hazardous when used with lithium; irreversible  toxic encephalopathy  has been reported. [ 100 ]
Indeed, these and other  antipsychotics  have been associated with an increased risk of lithium  neurotoxicity , even with low therapeutic lithium doses. [ 101 ] [ 102 ]


Classical psychedelics such as  psilocybin  and  LSD  may cause seizures if taken while using lithium, although further research is needed. [ 103 ]


Lithium toxicity, which is also called lithium overdose and lithium poisoning, is the condition of having too much lithium in the blood. This condition also happens in persons who are taking lithium in which the lithium levels are affected by  drug interactions  in the body.


In acute toxicity, people have primarily gastrointestinal symptoms such as vomiting and  diarrhea , which may result in  volume depletion . During acute toxicity, lithium distributes later into the central nervous system resulting in mild neurological symptoms, such as dizziness. [ 56 ]


In chronic toxicity, people have primarily neurological symptoms which include  nystagmus ,  tremor ,  hyperreflexia ,  ataxia , and  change in mental status . During chronic toxicity, the gastrointestinal symptoms seen in acute toxicity are less prominent. The symptoms are often vague and nonspecific. [ 104 ]


If the lithium toxicity is mild or moderate, lithium dosage is reduced or stopped entirely. If the toxicity is severe, lithium may need to be removed from the body.


The specific biochemical mechanism of lithium action in stabilizing mood is unknown. [ 5 ]


Upon ingestion, lithium becomes widely distributed in the  central nervous system  and interacts with a number of  neurotransmitters  and  receptors , decreasing  norepinephrine  release and increasing  serotonin  synthesis. [ 105 ]


Unlike many other  psychoactive drugs ,  Li +  typically produces no obvious psychotropic effects (such as  euphoria ) in normal individuals at therapeutic concentrations. [ 105 ]
Lithium may also increase the release of  serotonin  by neurons in the brain. [ 106 ]  In vitro studies performed on serotonergic neurons from rat  raphe nuclei  have shown that when these neurons are treated with lithium,  serotonin  release is enhanced during a  depolarization  compared to no lithium treatment and the same depolarization. [ 107 ]


Lithium both directly and indirectly inhibits  GSK3β (glycogen synthase kinase 3β)  which results in the activation of  mTOR . This leads to an increase in neuroprotective mechanisms by facilitating the  Akt signaling pathway . [ 108 ]  GSK-3β is a downstream target of monoamine systems. As such, it is directly implicated in cognition and mood regulation. [ 109 ] [ 108 ]  During mania, GSK-3β is activated via dopamine overactivity. [ 108 ]  GSK-3β inhibits the transcription factors  β-catenin  and cyclic AMP (cAMP) response element binding protein (CREB), by phosphorylation. This results in a decrease in the transcription of important genes encoding for  neurotrophins . [ 110 ] [ 111 ] [ 112 ]  In addition, several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium. [ 113 ] [ 114 ]  This hypothesis was supported by the low Ki of lithium for human pAp-phosphatase compatible within the range of therapeutic concentrations of lithium in the plasma of people (0.8–1 mM). The Ki of human pAp-phosphatase is ten times lower than that of  GSK3β (glycogen synthase kinase 3β) . Inhibition of pAp-phosphatase by lithium leads to increased levels of pAp (3′-5′ phosphoadenosine phosphate), which was shown to inhibit  PARP-1 . [ 115 ]


Another mechanism proposed in 2007 is that lithium may interact with  nitric oxide  (NO) signaling pathway in the central nervous system, which plays a crucial role in neural plasticity. The NO system could be involved in the antidepressant effect of lithium in the Porsolt forced swimming test in mice. [ 116 ] [ 117 ]  It was also reported that  NMDA receptor  blockage augments antidepressant-like effects of lithium in the mouse forced swimming test, [ 118 ]  indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of  learned helplessness .


Lithium possesses  neuroprotective  properties by preventing  apoptosis  and increasing cell longevity. [ 119 ]


Although the search for a novel lithium-specific receptor is ongoing, the high concentration of lithium compounds required to elicit a significant pharmacological effect leads mainstream researchers to believe that the existence of such a receptor is unlikely. [ 120 ]


Evidence suggests that  mitochondrial  dysfunction is present in patients with bipolar disorder. [ 119 ]
 Oxidative stress  and reduced levels of  anti-oxidants  (such as  glutathione ) lead to cell death. Lithium may protect against oxidative stress by up-regulating complexes I and II of the  mitochondrial electron transport chain . [ 119 ]


During mania, there is an increase in  neurotransmission  of  dopamine  that causes a secondary  homeostatic  down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression. [ 119 ]   Additionally, the post-synaptic actions of dopamine are mediated through  G-protein coupled receptors . Once dopamine is coupled to the G-protein receptors, it stimulates other secondary messenger systems that modulate neurotransmission. Studies found that in  autopsies  (which do not necessarily reflect living people), people with bipolar disorder had increased G-protein coupling compared to people without bipolar disorder. [ 119 ]  Lithium treatment alters the function of certain subunits of the dopamine-associated G-protein, which may be part of its mechanism of action. [ 119 ]


Glutamate  levels are observed to be elevated during  mania . Lithium is thought to provide long-term mood stabilization and have anti- manic  properties by modulating glutamate levels. [ 119 ]  It is proposed that lithium competes with magnesium for binding to  NMDA glutamate receptor ,  increasing the availability of glutamate in  post-synaptic   neurons , leading to a homeostatic increase in glutamate re-uptake which reduces glutamatergic transmission. [ 119 ]
The NMDA receptor is also affected by other  neurotransmitters  such as  serotonin  and  dopamine . Effects observed appear exclusive to lithium and have not been observed by other  monovalent  ions such as  rubidium  and  cesium . [ 119 ]


GABA  is an inhibitory  neurotransmitter  that plays an important role in regulating  dopamine  and  glutamate   neurotransmission . [ 119 ]  It was found that patients with bipolar disorder had lower GABA levels, which results in  excitotoxicity  and can cause  apoptosis  (cell loss). Lithium has been shown to increase the level of GABA in plasma and cerebral spinal fluid. [ 121 ]  Lithium counteracts these degrading processes by decreasing pro-apoptotic  proteins  and stimulating release of  neuroprotective  proteins. [ 119 ]  Lithium's regulation of both excitatory dopaminergic and glutamatergic systems through GABA may play a role in its mood-stabilizing effects. [ 122 ]


Lithium's therapeutic effects are thought to be partially attributable to its interactions with several signal transduction mechanisms. [ 123 ]  The  cyclic AMP  secondary messenger system is shown to be modulated by lithium. Lithium was found to increase the basal levels of cyclic AMP but impair receptor-coupled stimulation of cyclic AMP production. [ 119 ]  It is hypothesized that the dual effects of lithium are due to the inhibition of  G-proteins  that mediate cyclic AMP production. [ 119 ]  Over a long period of lithium treatment, cyclic AMP and  adenylate cyclase  levels are further changed by  gene transcription factors . [ 119 ]


Lithium treatment has been found to inhibit the enzyme  inositol monophosphatase , involved in degrading inositol monophosphate to inositol required in  PIP 2  synthesis. This leads to lower levels of  inositol triphosphate , created by decomposition of PIP 2 . [ 124 ]  This effect has been suggested to be further enhanced with an inositol triphosphate  reuptake inhibitor .  Inositol  disruptions have been linked to memory impairment and depression. It is known with good certainty that signals from the receptors coupled to the  phosphoinositide   signal transduction  are affected by lithium. [ 125 ]   myo-inositol  is also regulated by the high affinity  sodium mI transport system  (SMIT). Lithium is hypothesized to inhibit mI entering the cells and mitigate the function of SMIT. [ 119 ]  Reductions of cellular levels of  myo-inositol  results in the inhibition of the  phosphoinositide cycle . [ 119 ]


Lithium's actions on Gsk3 result in activation of CREB, leading to higher expression of BDNF.  (Valproate, another mood stabilizer, also increases the expression of BDNF.) As expected of increased BDNF expression, chronic lithium treatment leads to increased  grey matter  volume in brain areas implicated in emotional processing and cognitive control. [ 126 ]  Bipolar patients treated with lithium also have higher  white matter  integrity compared to those taking other drugs. [ 127 ]


Lithium also increases the expression of  mesencephalic astrocyte-derived neurotrophic factor  (MANF), another  neurotrophic factor , via the  AP-1 transcription factor . MANF is able to regulate  proteostasis  by interacting with  GRP78 , a protein involved in the  unfolded protein response . [ 128 ]


Lithium was first used in the 19th century as a treatment for  gout  after scientists discovered that, at least in the laboratory, lithium could dissolve  uric acid  crystals isolated from the kidneys. The levels of lithium needed to dissolve urate in the body, however, were toxic. [ 129 ]  Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders,  Carl Lange  in Denmark [ 10 ]  and  William Alexander Hammond  in New York City [ 11 ]  used lithium to treat mania from the 1870s onwards.


By the turn of the 20th century, as theory regarding mood disorders evolved and so-called "brain gout" disappeared as a medical entity, the use of lithium in psychiatry was largely abandoned; however, several lithium preparations were still produced for the control of renal calculi and  uric acid diathesis . [ 19 ]  As accumulating knowledge indicated a role for excess sodium intake in  hypertension  and  heart disease , lithium salts were prescribed to patients for use as a replacement for dietary  table salt  ( sodium chloride ). This practice and the sale of lithium itself were both banned in the United States in February 1949, following the publication of reports detailing side effects and deaths. [ 130 ]


Also in 1949, the Australian psychiatrist  John Cade  and Australian  biochemist   Shirley Andrews  rediscovered the usefulness of lithium salts in treating mania while working at the Royal Park Psychiatric Hospital in  Victoria. [ 131 ]  They were injecting rodents with urine extracts taken from manic patients in an attempt to isolate a metabolic compound which might be causing mental symptoms. Since uric acid in gout was known to be psychoactive, ( adenosine receptors  on neurons are stimulated by it;  caffeine  blocks them), they needed soluble urate for a control. They used lithium urate, already known to be the most soluble urate compound, and observed that it caused the rodents to become tranquil. Cade and Andrews traced the effect to the lithium-ion itself, and after Cade ingested lithium himself to ensure its safety in humans, he proposed lithium salts as  tranquilizers . He soon succeeded in controlling mania in chronically hospitalized patients with them. This was one of the first successful applications of a drug to treat mental illness, and it opened the door for the development of medicines for other mental problems in the next decades. [ 132 ]


The rest of the world was slow to adopt this treatment, largely because of deaths that resulted from even relatively minor overdosing, including those reported from the use of  lithium chloride  as a substitute for table salt. Largely through the research and other efforts of Denmark's  Mogens Schou  and  Paul Baastrup  in Europe, [ 129 ]  and  Samuel Gershon  and  Baron Shopsin  in the U.S., this resistance was slowly overcome. Following the recommendation of the  APA  Lithium Task Force  (William Bunney ,  Irvin Cohen  (Chair),  Jonathan Cole ,  Ronald R. Fieve , Samuel Gershon, Robert Prien, and Joseph Tupin [ 133 ] ), the application of lithium in manic illness was approved by the United States  Food and Drug Administration  in 1970, [ 134 ]  becoming the 50th nation to do so. [ 19 ]


Lithium has now become a part of Western popular culture. Characters in  Pi ,   Premonition ,  Stardust Memories ,   American Psycho ,  Garden State , and  An Unmarried Woman  all take lithium. It's the chief constituent of the calming drug in  Ira Levin 's dystopian  This Perfect Day .  Sirius XM  Satellite Radio in North America has a 1990s alternative rock station called Lithium, and several songs refer to the use of lithium as a mood stabilizer. These include: "Equilibrium met Lithium" by  South African  artist  Koos Kombuis , " Lithium " by  Evanescence , " Lithium " by  Nirvana , "Lithium and a Lover" by  Sirenia , "Lithium Sunset", from the album  Mercury Falling  by  Sting , [ 135 ]  and "Lithium" by  Thin White Rope .


As with  cocaine in Coca-Cola , lithium was widely marketed as one of several  patent medicine  products popular in the late 19th and early 20th centuries and was the medicinal ingredient of a refreshment beverage.  Charles Leiper Grigg , who launched his St. Louis-based company The Howdy Corporation, invented a formula for a  lemon-lime  soft drink in 1920. The product, originally named "Bib-Label Lithiated Lemon-Lime Soda", was launched two weeks before the  Wall Street Crash of 1929 . [ 136 ]  It contained the  mood stabilizer   lithium citrate , and was one of many patent medicine products popular in the late-19th and early-20th centuries. [ 137 ]  Its name was soon changed to  7 Up . All American beverage makers were forced to remove lithium from beverages in 1948. Despite the ban, in 1950, the  Painesville Telegraph  still carried an advertisement for a lithiated lemon beverage. [ 138 ]


Lithium carbonate  ( Li 2 CO 3 ) is the most commonly used form of  lithium salts , a  carbonic acid  involving the  lithium element  and a  carbonate ion . Other lithium salts are also used as medication, such as  lithium citrate  ( Li 3 C 6 H 5 O 7 ),  lithium sulfate ,  lithium chloride , and  lithium orotate . [ 139 ] [ 140 ]   Nanoparticles  and  microemulsions  have also been invented as  drug delivery  mechanisms. As of 2020, there is a lack of evidence that alternate formulations or salts of lithium would reduce the need for monitoring serum lithium levels or lower systemic toxicity. [ 139 ]


As of 2017 lithium was marketed under many brand names worldwide, including Cade, Calith, Camcolit, Carbolim, Carbolit, Carbolith, Carbolithium, Carbolitium, Carbonato de Litio, Carboron, Ceglution, Contemnol, Efadermin (Lithium and Zinc Sulfate), Efalith (Lithium and Zinc Sulfate), Elcab, Eskalit, Eskalith, Frimania, Hypnorex, Kalitium, Karlit, Lalithium, Li-Liquid, Licarb, Licarbium, Lidin, Ligilin, Lilipin, Lilitin, Limas, Limed, Liskonum, Litarex, Lithane, Litheum, Lithicarb, Lithii carbonas, Lithii citras, Lithioderm, Lithiofor, Lithionit, Lithium, Lithium aceticum, Lithium asparagicum, Lithium Carbonate, Lithium Carbonicum, Lithium Citrate, Lithium DL-asparaginat-1-Wasser, Lithium gluconicum, Lithium-D-gluconat, Lithiumcarbonaat, Lithiumcarbonat, Lithiumcitrat, Lithiun, Lithobid, Lithocent, Lithotabs, Lithuril, Litiam, Liticarb, Litijum, Litio, Litiomal, Lito, Litocarb, Litocip, Maniprex, Milithin, Neurolepsin, Plenur, Priadel, Prianil, Prolix, Psicolit, Quilonium, Quilonorm, Quilonum, Téralithe, and Theralite. [ 1 ]


Tentative evidence in  Alzheimer's disease  showed that lithium may slow progression. [ 141 ] [ 142 ]  It has been studied for its potential use in the treatment of  amyotrophic lateral sclerosis  (ALS), but a study showed lithium had no effect on ALS outcomes. [ 143 ]


Lithium toxicity , also known as  lithium overdose , is the condition of having too much  lithium . Symptoms may include a tremor, increased reflexes, trouble walking, kidney problems, and an  altered level of consciousness . Some symptoms may last for a year after levels return to normal. Complications may include  serotonin syndrome . [ 1 ]


Lithium toxicity can occur due to excessive intake or decreased excretion. [ 1 ]  Excessive intake may be either a  suicide attempt  or accidental. [ 1 ]  Decreased excretion may occur as a result of  dehydration  such as from  vomiting  or  diarrhea , a  low sodium diet , or from  kidney problems . [ 1 ]  The diagnosis is generally based on symptoms and supported by a lithium level in blood serum of greater than 1.2 mEq/L. [ 1 ] [ 2 ]


Gastric lavage  and  whole bowel irrigation  may be useful if done early. [ 1 ]   Activated charcoal  is not effective. [ 1 ]  For severe toxicity  hemodialysis  is recommended. [ 1 ]  The risk of death is generally low. [ 3 ]  Acute toxicity generally has better outcomes than chronic toxicity. [ 4 ]  In the United States about 5,000 cases are reported to  poison control centers  a year. [ 2 ]  Lithium toxicity was first described in 1898. [ 1 ]


Symptoms of lithium toxicity can be mild, moderate, or severe. [ 1 ]


Mild symptoms include nausea, feeling tired, and tremor occur at a level of 1.5 to 2.5 mEq/L in blood serum. Moderate symptoms include confusion, an increased heart rate, and low muscle tone occur at a level of 2.5 to 3.5 mEq/L. [ 1 ]  Severe symptoms include coma, seizures, low blood pressure and increased body temperature which occur at a lithium concentration greater than 3.5 mEq/L. [ 1 ]  When lithium overdoses produce neurological deficits or cardiac toxicity, the symptoms are considered serious and can be fatal. [ 5 ]


In acute toxicity, people have primarily gastrointestinal symptoms such as  vomiting  and  diarrhea , which may result in  volume depletion . During acute toxicity, lithium distributes later into the central nervous system causing dizziness and other mild neurological symptoms. [ 6 ]


In chronic toxicity, people have primarily neurological symptoms which include  nystagmus ,  tremor ,  hyperreflexia ,  ataxia , and  change in mental status . During chronic toxicity, the gastrointestinal symptoms seen in acute toxicity are less prominent. The symptoms are often vague and nonspecific. [ 7 ]


In acute on chronic toxicity [ clarification needed ] , people have symptoms of both acute and chronic toxicity.


People who survive an intoxication episode may develop persistent health problems. [ 8 ]  This group of persistent health symptoms are called syndrome of irreversible lithium-effectuated  neurotoxicity  (SILENT). [ 9 ]  The syndrome presents with irreversible neurological and neuro-psychiatric effects. [ 10 ]  The neurological signs are  cerebellar  dysfunction,  extrapyramidal symptoms , and  brainstem  dysfunction. [ 11 ]  The neuro-psychiatric findings present with memory deficits,  cognitive deficits, and  sub-cortical dementia . For a diagnosis, the syndrome requires the absence of prior symptoms and persistence of symptoms for greater than 2 months after cessation of lithium. [ 12 ]


Lithium is readily absorbed from the  gastrointestinal tract . [ 5 ]  It is distributed to the body with higher levels in the kidney,  thyroid , and bone as compared to other tissues. Since lithium is almost exclusively excreted by the  kidneys , people with preexisting  chronic kidney disease  are at high risk of developing lithium intoxication. [ 13 ]  The drug itself is also known to be  nephrotoxic , opening up the possibility of spontaneous emergence of toxicity at doses that were previously well-tolerated. Lithium toxicity can be mistaken for other syndromes associated with antipsychotic use, such as  serotonin syndrome  because lithium increases  serotonin  metabolites in the  cerebrospinal fluid . [ 14 ]


There are several drug interactions with lithium. Interactions can occur from  typical antipsychotics  or  atypical antipsychotics . In particular, certain drugs enhance lithium levels by increasing renal re-absorption at the proximal tubule. These drugs are  angiotensin-converting enzyme inhibitors ,  non-steroidal anti-inflammatory drugs  and  thiazide diuretics . [ 13 ]


The diagnosis is generally based on symptoms and supported by a lithium level blood level. [ 1 ] [ 2 ]  Blood levels are most useful six to twelve hours after the last dose. [ 2 ]  The normal blood serum lithium level in those on treatment is between 0.6-1.2 mEq/L. [ 1 ]  Some blood tubes contain  lithium heparin  which may result in falsely elevated results. [ 2 ]


When lithium toxicity is suspected tests may include:


Imaging tests are not helpful.


If the person's lithium toxicity is mild or moderate, lithium dosage is reduced or stopped entirely. [ 13 ]  If the toxicity is severe, lithium may need to be removed from the body. The removal of lithium is done in a  hospital   emergency department . It may involve:


Magnesium  is an essential element in biological systems. Magnesium occurs typically as the Mg 2+  ion. It is an essential mineral  nutrient  (i.e., element) for life [ 1 ] [ 2 ] [ 3 ] [ 4 ]  and is present in every  cell  type in every organism. For example,  adenosine triphosphate  (ATP), the main source of energy in cells, must bind to a magnesium ion in order to be biologically active. What is called ATP is often actually Mg-ATP. [ 5 ]  As such, magnesium plays a role in the stability of all  polyphosphate  compounds in the cells, including those associated with the synthesis of  DNA  and  RNA . [ citation needed ]


Over 300  enzymes  require the presence of magnesium ions for their catalytic action, including  all  enzymes utilizing or synthesizing ATP, or those that use other  nucleotides  to synthesize DNA and RNA. [ 6 ]


In plants, magnesium is necessary for synthesis of  chlorophyll  and  photosynthesis . [ citation needed ]


A balance of magnesium is vital to the well-being of all organisms. Magnesium is a relatively abundant ion in Earth's crust and mantle and is highly bioavailable in the  hydrosphere . This availability, in combination with a useful and very unusual chemistry, may have led to its utilization in evolution as an ion for signaling, enzyme activation, and  catalysis . However, the unusual nature of ionic magnesium has also led to a major challenge in the use of the ion in biological systems. Biological membranes are impermeable to magnesium (and other ions), so  transport proteins  must facilitate the flow of magnesium, both into and out of cells and intracellular compartments. [ 7 ]


Inadequate magnesium intake frequently causes muscle  spasms , and has been associated with  cardiovascular disease ,  diabetes ,  high blood pressure ,  anxiety  disorders,  migraines ,  osteoporosis , and  cerebral infarction . [ 8 ] [ 9 ]  Acute deficiency (see  hypomagnesemia ) is rare, and is more common as a drug side-effect (such as chronic alcohol or diuretic use) than from low food intake per se, but it can occur in people fed intravenously for extended periods of time. [ citation needed ]


The most common symptom of excess oral magnesium intake is  diarrhea . Supplements based on  amino acid   chelates  (such as  glycinate ,  lysinate  etc.) are much better-tolerated by the  digestive system  and do not have the  side-effects  of the older compounds used, while  sustained-release   dietary supplements  prevent the occurrence of diarrhea. [ citation needed ]  Since the kidneys of adult humans excrete excess magnesium efficiently, oral magnesium poisoning in adults with normal  renal function  is very rare. Infants, which have less ability to excrete excess magnesium even when healthy, should not be given magnesium supplements, except under a physician's care. [ citation needed ]


Pharmaceutical preparations with magnesium  are used to treat conditions including  magnesium deficiency  and  hypomagnesemia , as well as  eclampsia . [ 10 ]  Such preparations are usually in the form of  magnesium sulfate  or chloride when given  parenterally . Magnesium is absorbed with reasonable efficiency (30% to 40%) by the body from any soluble magnesium salt, such as the chloride or citrate. Magnesium is similarly absorbed from  Epsom salts , although the sulfate in these salts adds to their laxative effect at higher doses. Magnesium absorption from the insoluble oxide and hydroxide salts ( milk of magnesia ) is erratic and of poorer efficiency, since it depends on the neutralization and solution of the salt by the acid of the stomach, which may not be (and usually is not) complete.


Magnesium orotate  may be used as adjuvant therapy in patients on optimal treatment for severe  congestive heart failure , increasing survival rate and improving clinical symptoms and patient's  quality of life . [ 11 ]


In 2022, magnesium salts were the 207th most commonly prescribed medication in the United States, with more than 1   million prescriptions. [ 12 ] [ 13 ]


Magnesium can affect muscle relaxation through direct action on cell membranes. Mg 2+  ions close certain types of  calcium channels , which conduct positively charged  calcium ions  into  neurons . With an excess of magnesium, more channels will be blocked and nerve cells activity will decrease. [ 14 ] [ 15 ]


Intravenous magnesium sulphate is used in treating  pre-eclampsia . [ 16 ]  For other than pregnancy-related hypertension, a meta-analysis of 22 clinical trials with dose ranges of 120 to 973 mg/day and a mean dose of 410 mg, concluded that magnesium supplementation had a small but statistically significant effect, lowering systolic blood pressure by 3–4 mm Hg and diastolic blood pressure by 2–3 mm Hg. The effect was larger when the dose was more than 370 mg/day. [ 17 ]


Higher dietary intakes of magnesium correspond to lower diabetes incidence. [ 18 ]  For people with diabetes or at high risk of diabetes, magnesium supplementation lowers fasting glucose. [ 19 ]


Magnesium is essential as part of the process that generates  adenosine triphosphate . [ 20 ] [ 21 ]


Mitochondria  are often referred to as the "powerhouses of the cell" because their primary role is generating energy for cellular processes. They achieve this by breaking down  nutrients , primarily  glucose , through a series of chemical reactions known as  cellular respiration . This process ultimately produces adenosine triphosphate (ATP), the cell's main energy currency.


Magnesium and  vitamin D  have a synergistic relationship in the body, meaning they work together to optimize each other's functions: [ 22 ] [ 23 ]


Overall, maintaining adequate levels of both magnesium and vitamin D is essential for optimal health and well-being.


It is theorized that the process of making testosterone from cholesterol, needs magnesium to function properly. [ 24 ]


Studies have shown that significant gains in testosterone occur after taking 10 mg magnesium/kg body weight/day. [ 25 ]


The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and  Recommended Dietary Allowances  (RDAs) for magnesium in 1997. If there is not sufficient information to establish EARs and RDAs, an estimate designated Adequate Intake (AI) is used instead. The current EARs for magnesium for women and men ages 31 and up are 265 mg/day and 350 mg/day, respectively. The RDAs are 320 and 420 mg/day. RDAs are higher than EARs so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy is 350 to 400 mg/day depending on age of the woman. RDA for lactation ranges 310 to 360 mg/day for same reason. For children ages 1–13 years, the RDA increases with age from 65 to 200 mg/day. As for safety, the IOM also sets  Tolerable upper intake levels  (ULs) for vitamins and minerals when evidence is sufficient. In the case of magnesium the UL is set at 350 mg/day. The UL is specific to magnesium consumed as a dietary supplement, the reason being that too much magnesium consumed at one time can cause diarrhea. The UL does not apply to food-sourced magnesium. Collectively the EARs, RDAs and ULs are referred to as  Dietary Reference Intakes . [ 26 ]


* = Adequate intake


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 and men ages 18 and older, the AIs are set at 300 and 350 mg/day, respectively. AIs for pregnancy and lactation are also 300 mg/day. For children ages 1–17 years, the AIs increase with age from 170 to 250 mg/day. These AIs are lower than the U.S. RDAs. [ 28 ]  The European Food Safety Authority reviewed the same safety question and set its UL at 250 mg/day –  lower than the U.S. value. [ 29 ]  The magnesium UL is unique in that it is lower than some of the RDAs. It applies to intake from a pharmacological agent or dietary supplement only and does not include intake from food and water.


For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of daily value (%DV). For magnesium labeling purposes, 100% of the daily value was 400 mg, but as of May 27, 2016, it was revised to 420 mg to bring it into agreement with the RDA. [ 30 ] [ 31 ]  A table of the old and new adult Daily Values is provided at  Reference Daily Intake .


Green vegetables  such as  spinach  provide magnesium because of the abundance of  chlorophyll  molecules, which contain the ion.  Nuts  (especially  Brazil nuts ,  cashews  and  almonds ),  seeds  (e.g.,  pumpkin seeds ),  dark chocolate , roasted  soybeans ,  bran , and some  whole grains  are also good sources of magnesium. [ 32 ]


Although many foods contain magnesium, it is usually found in low levels. As with most nutrients, daily needs for magnesium are unlikely to be met by one serving of any single food. Eating a wide variety of fruits, vegetables, and grains will help ensure adequate intake of magnesium.


Because magnesium readily dissolves in water, refined foods, which are often processed or cooked in water and dried, in general, are poor sources of the nutrient. For example,  whole-wheat bread  has twice as much magnesium as white bread because the magnesium-rich germ and bran are removed when white flour is processed. The table of food sources of magnesium suggests many dietary sources of magnesium.


"Hard" water  can also provide magnesium, but  "soft" water  contains less of the ion. Dietary surveys do not assess magnesium intake from water, which may lead to underestimating total magnesium intake and its variability.


Too much magnesium may make it difficult for the body to absorb  calcium . Not enough magnesium can lead to  hypomagnesemia  as described above, with irregular heartbeats, high blood pressure (a sign in humans but not some experimental animals such as rodents), insomnia, and muscle spasms ( fasciculation ). However, as noted, symptoms of low magnesium from pure dietary deficiency are thought to be rarely encountered.


Following are some foods and the amount of magnesium in them: [ 33 ]


In  animals , it has been shown that different cell types maintain different concentrations of magnesium. [ 35 ] [ 36 ] [ 37 ] [ 38 ]  It seems likely that the same is true for  plants . [ 39 ] [ 40 ]  This suggests that different cell types may regulate influx and efflux of magnesium in different ways based on their unique metabolic needs. Interstitial and systemic concentrations of free magnesium must be delicately maintained by the combined processes of buffering (binding of ions to proteins and other molecules) and muffling (the transport of ions to storage or extracellular spaces [ 41 ] ).


In plants, and more recently in animals, magnesium has been recognized as an important signaling ion, both activating and mediating many biochemical reactions. The best example of this is perhaps the regulation of  carbon  fixation in  chloroplasts  in the  Calvin cycle . [ 42 ] [ 43 ]


Magnesium is very important in cellular function. Deficiency of the  nutrient  causes disease of the affected organism. In single-cell organisms such as  bacteria  and  yeast , low levels of magnesium manifests in greatly reduced growth rates. In magnesium transport  knockout  strains of bacteria, healthy rates are maintained only with exposure to very high external concentrations of the ion. [ 44 ] [ 45 ]  In yeast,  mitochondrial  magnesium deficiency also leads to disease. [ 46 ]


Plants deficient in magnesium show stress responses. The first observable signs of both magnesium starvation and overexposure in plants is a decrease in the rate of  photosynthesis . This is due to the central position of the Mg 2+  ion in the  chlorophyll  molecule. The later effects of magnesium deficiency on plants are a significant reduction in growth and reproductive viability. [ 4 ]  Magnesium can also be toxic to plants, although this is typically seen only in  drought  conditions. [ 47 ] [ 48 ]


In animals, magnesium deficiency ( hypomagnesemia ) is seen when the environmental availability of magnesium is low. In ruminant animals, particularly vulnerable to magnesium availability in pasture grasses, the condition is known as 'grass tetany'. Hypomagnesemia is identified by a loss of balance due to muscle weakness. [ 49 ]  A number of genetically attributable hypomagnesemia disorders have also been identified in humans. [ 50 ] [ 51 ] [ 52 ] [ 53 ]


Overexposure to magnesium may be toxic to individual cells, though these effects have been difficult to show experimentally. [ citation needed ]   Hypermagnesemia , an overabundance of magnesium in the blood, is usually caused by loss of  kidney  function. Healthy animals rapidly excrete excess magnesium in the urine and stool. [ 54 ]  Urinary magnesium is called  magnesuria . Characteristic concentrations of magnesium in model organisms are: in  E. coli  30-100mM (bound), 0.01-1mM (free), in budding yeast 50mM, in mammalian cell 10mM (bound), 0.5mM (free) and in blood plasma 1mM. [ 55 ]


Mg 2+  is the fourth-most-abundant  metal   ion  in cells (per  moles ) and the most abundant free divalent cation — as a result, it is deeply and intrinsically woven into cellular  metabolism . Indeed, Mg 2+ -dependent  enzymes  appear in virtually every metabolic pathway: Specific binding of Mg 2+  to biological membranes is frequently observed, Mg 2+  is also used as a signalling molecule, and much of nucleic acid biochemistry requires Mg 2+ , including all reactions that require release of energy from ATP. [ 56 ] [ 57 ] [ 43 ]  In nucleotides, the triple-phosphate moiety of the compound is invariably stabilized by association with Mg 2+  in all enzymatic processes.


In photosynthetic organisms, Mg 2+  has the additional vital role of being the  coordinating ion  in the  chlorophyll  molecule. This role was discovered by  Richard Willstätter , who received the Nobel Prize in Chemistry 1915 for the purification and structure of chlorophyll binding with sixth number of carbon


The chemistry of the Mg 2+  ion, as applied to enzymes, uses the full range of this ion's unusual reaction chemistry to fulfill a range of functions. [ 56 ] [ 58 ] [ 59 ] [ 60 ]  Mg 2+  interacts with substrates, enzymes, and occasionally both (Mg 2+  may form part of the active site). In general, Mg 2+  interacts with substrates through inner sphere coordination, stabilising anions or reactive intermediates, also including binding to ATP and activating the molecule to nucleophilic attack. When interacting with enzymes and other proteins, Mg 2+  may bind using inner or outer sphere coordination, to either alter the conformation of the enzyme or take part in the chemistry of the catalytic reaction. In either case, because Mg 2+  is only rarely fully dehydrated during ligand binding, it may be a water molecule associated with the Mg 2+  that is important rather than the ion itself. The  Lewis acidity  of Mg 2+  ( p K a  11.4) is used to allow both hydrolysis and condensation reactions (most common ones being phosphate ester hydrolysis and phosphoryl transfer) that would otherwise require pH values greatly removed from physiological values.


ATP  (adenosine triphosphate), the main source of energy in cells, must be bound to a magnesium ion in order to be biologically active. What is called ATP is often actually Mg-ATP. [ 5 ]


Nucleic acids  have an important range of interactions with Mg 2+ . The binding of Mg 2+  to  DNA  and  RNA  stabilises structure; this can be observed in the increased melting temperature ( T m ) of double-stranded DNA in the presence of Mg 2+ . [ 56 ]  In addition,  ribosomes  contain large amounts of Mg 2+  and the stabilisation provided is essential to the complexation of this ribo-protein. [ 61 ]  A large number of enzymes involved in the biochemistry of nucleic acids bind Mg 2+  for activity, using the ion for both activation and catalysis. Finally, the  autocatalysis  of many  ribozymes  (enzymes containing only RNA) is Mg 2+  dependent (e.g. the yeast mitochondrial group II self splicing introns [ 62 ] ).


Magnesium ions can be critical in maintaining the positional integrity of closely clustered phosphate groups. These clusters appear in numerous and distinct parts of the  cell nucleus  and  cytoplasm . For instance, hexahydrated Mg 2+  ions bind in the deep  major groove  and at the outer mouth of A-form nucleic acid  duplexes . [ 63 ]


Biological  cell membranes  and  cell walls  are polyanionic surfaces. This has important implications for the transport of ions, in particular because it has been shown that different membranes preferentially bind different ions. [ 56 ]  Both Mg 2+  and Ca 2+  regularly stabilize membranes by the cross-linking of  carboxylated  and  phosphorylated  head groups of lipids. However, the envelope membrane of  E. coli  has also been shown to bind Na + , K + , Mn 2+  and Fe 3+ . The transport of ions is dependent on both the concentration gradient of the ion and the electric potential (ΔΨ) across the membrane, which will be affected by the charge on the membrane surface. For example, the specific binding of Mg 2+  to the  chloroplast  envelope has been implicated in a loss of photosynthetic efficiency by the blockage of K +  uptake and the subsequent acidification of the chloroplast stroma. [ 42 ]


The Mg 2+  ion tends to bind only weakly to  proteins  ( K a  ≤ 10 5 [ 56 ] ) and this can be exploited by the cell to switch  enzymatic  activity on and off by changes in the local concentration of Mg 2+ . Although the concentration of free cytoplasmic Mg 2+  is on the order of 1 mmol/L, the total Mg 2+  content of animal cells is 30 mmol/L [ 64 ]  and in plants the content of leaf endodermal cells has been measured at values as high as 100 mmol/L (Stelzer  et al. , 1990), much of which buffered in storage compartments. The cytoplasmic concentration of free Mg 2+  is buffered by binding to  chelators  (e.g., ATP), but also, what is more important, it is buffered by storage of Mg 2+  in intracellular compartments. [ citation needed ]  The transport of Mg 2+  between intracellular compartments may be a major part of regulating enzyme activity. The interaction of Mg 2+  with proteins must also be considered for the transport of the ion across biological membranes. [ citation needed ]


In biological systems, only  manganese  (Mn 2+ ) is readily capable of replacing Mg 2+ , but only in a limited set of circumstances. Mn 2+  is very similar to Mg 2+  in terms of its chemical properties, including inner and outer shell complexation. Mn 2+  effectively binds ATP and allows hydrolysis of the energy molecule by most ATPases. Mn 2+  can also replace Mg 2+  as the activating ion for a number of Mg 2+ -dependent enzymes, although some enzyme activity is usually lost. [ 56 ]  Sometimes such enzyme metal preferences vary among closely related species: For example, the  reverse transcriptase  enzyme of  lentiviruses  like  HIV ,  SIV  and  FIV  is typically dependent on Mg 2+ , whereas the analogous enzyme for other  retroviruses  prefers Mn 2+ .


The use of radioactive tracer elements in ion uptake assays allows the calculation of km, Ki and Vmax and determines the initial change in the ion content of the cells.  28 Mg decays by the emission of a high-energy beta or gamma particle, which can be measured using a scintillation counter. However, the radioactive half-life of  28 Mg, the most stable of the radioactive magnesium isotopes, is only 21 hours. This severely restricts the experiments involving the nuclide. Also, since 1990, no facility has routinely produced  28 Mg, and the price per mCi is now predicted to be approximately US$30,000. [ 65 ]  The chemical nature of Mg 2+  is such that it is closely approximated by few other cations. [ 66 ]  However, Co 2+ , Mn 2+  and Ni 2+  have been used successfully to mimic the properties of Mg 2+  in some enzyme reactions, and radioactive forms of these elements have been employed successfully in cation transport studies. The difficulty of using metal ion replacement in the study of enzyme function is that the relationship between the enzyme activities with the replacement ion compared to the original is very difficult to ascertain. [ 66 ]


A number of chelators of divalent cations have different fluorescence spectra in the bound and unbound states. [ 67 ]  Chelators for Ca 2+  are well established, have high affinity for the cation, and low interference from other ions. Mg 2+  chelators lag behind and the major fluorescence dye for Mg 2+  (mag-fura 2 [ 68 ] ) actually has a higher affinity for Ca 2+ . [ 69 ]  This limits the application of this dye to cell types where the resting level of Ca 2+  is < 1 μM and does not vary with the experimental conditions under which Mg 2+  is to be measured. Recently, Otten  et al.  (2001) have described work into a new class of compounds that may prove more useful, having significantly better binding affinities for Mg 2+ . [ 70 ]  The use of the fluorescent dyes is limited to measuring the free Mg 2+ . If the ion concentration is buffered by the cell by chelation or removal to subcellular compartments, the measured rate of uptake will give only minimum values of km and Vmax. [ citation needed ]


First, ion-specific microelectrodes can be used to measure the internal free ion concentration of cells and organelles. The major advantages are that readings can be made from cells over relatively long periods of time, and that unlike dyes very little extra ion buffering capacity is added to the cells. [ 71 ]


Second, the technique of two-electrode voltage-clamp allows the direct measurement of the ion flux across the membrane of a cell. [ 72 ]  The membrane is held at an electric potential and the responding current is measured. All ions passing across the membrane contribute to the measured current. [ citation needed ]


Third, the technique of patch-clamp uses isolated sections of natural or artificial membrane in much the same manner as voltage-clamp but without the secondary effects of a cellular system. Under ideal conditions the conductance of individual channels can be quantified. This methodology gives the most direct measurement of the action of ion channels. [ 72 ]


Flame  atomic absorption spectroscopy  (AAS) determines the total magnesium content of a biological sample. [ 67 ]  This method is destructive; biological samples must be broken down in concentrated acids to avoid clogging the fine nebulising apparatus. [ citation needed ]  Beyond this, the only limitation is that samples must be in a volume of approximately 2 mL and at a concentration range of 0.1 – 0.4 μmol/L for optimum accuracy. [ citation needed ]  As this technique cannot distinguish between Mg 2+  already present in the cell and that taken up during the experiment, only content not uptaken can be quantified. [ citation needed ]


Inductively coupled plasma  (ICP) using either the  mass spectrometry  (MS) or  atomic emission spectroscopy  (AES) modifications also allows the determination of the total ion content of biological samples. [ 73 ]


The chemical and biochemical properties of Mg 2+  present the cellular system with a significant challenge when transporting the ion across biological membranes. The dogma of ion transport states that the transporter recognises the ion then progressively removes the water of hydration, removing most or all of the water at a selective pore before releasing the ion on the far side of the membrane. [ 74 ]  Due to the properties of Mg 2+ , large volume change from hydrated to bare ion, high energy of hydration and very low rate of ligand exchange in the inner  coordination sphere , these steps are probably more difficult than for most other ions. To date, only the ZntA protein of  Paramecium  has been shown to be a Mg 2+  channel. [ 75 ]  The mechanisms of Mg 2+  transport by the remaining proteins are beginning to be uncovered with the first three-dimensional structure of a Mg 2+  transport complex being solved in 2004. [ 76 ]


The  hydration shell  of the Mg 2+  ion has a very tightly bound inner shell of six water molecules and a relatively tightly bound second shell containing 12–14 water molecules (Markham  et al. , 2002). Thus, it is presumed that recognition of the Mg 2+  ion requires some mechanism to interact initially with the hydration shell of Mg 2+ , followed by a direct recognition/binding of the ion to the protein. [ 65 ]


In spite of the mechanistic difficulty, Mg 2+  must be transported across membranes, and a large number of Mg 2+  fluxes across membranes from a variety of systems have been described. [ 77 ]  However, only a small selection of Mg 2+  transporters have been characterised at the molecular level.


Magnesium   ions  (Mg 2+ ) in  cellular biology  are usually in almost all senses opposite to  Ca 2+  ions, because they are  bivalent  too, but have greater  electronegativity  and thus exert greater pull on water molecules, preventing passage through the channel (even though the magnesium itself is smaller). Thus, Mg 2+  ions block Ca 2+  channels such as ( NMDA channels ) and have been shown to affect gap junction channels forming  electrical synapses .


The previous sections have dealt in detail with the chemical and biochemical aspects of Mg 2+  and its transport across cellular membranes. This section will apply this knowledge to aspects of whole plant physiology, in an attempt to show how these processes interact with the larger and more complex environment of the multicellular organism.


Mg 2+  is essential for plant growth and is present in higher plants in amounts on the order of 80 μmol g −1  dry weight. [ 4 ]  The amounts of Mg 2+  vary in different parts of the plant and are dependent upon nutritional status. In times of plenty, excess Mg 2+  may be stored in vascular cells (Stelzer  et al. , 1990; [ 40 ]  and in times of starvation Mg 2+  is redistributed, in many plants, from older to newer leaves. [ 4 ] [ 78 ]


Mg 2+  is taken up into plants via the roots. Interactions with other cations in the  rhizosphere  can have a significant effect on the uptake of the ion.(Kurvits and Kirkby, 1980; [ 79 ]  The structure of root cell walls is highly permeable to water and ions, and hence ion uptake into root cells can occur anywhere from the root hairs to cells located almost in the centre of the root (limited only by the  Casparian strip ). Plant cell walls and membranes carry a great number of negative charges, and the interactions of cations with these charges is key to the uptake of cations by root cells allowing a local concentrating effect. [ 80 ]  Mg 2+  binds relatively weakly to these charges, and can be displaced by other cations, impeding uptake and causing deficiency in the plant.


Within individual plant cells, the Mg 2+  requirements are largely the same as for all cellular life; Mg 2+  is used to stabilise membranes, is vital to the utilisation of ATP, is extensively involved in the nucleic acid biochemistry, and is a cofactor for many enzymes (including the ribosome). Also, Mg 2+  is the coordinating ion in the chlorophyll molecule. It is the intracellular compartmentalisation of Mg 2+  in plant cells that leads to additional complexity. Four compartments within the plant cell have reported interactions with Mg 2+ . Initially, Mg 2+  will enter the cell into the cytoplasm (by an as yet unidentified system), but free Mg 2+  concentrations in this compartment are tightly regulated at relatively low levels (≈2 mmol/L) and so any excess Mg 2+  is either quickly exported or stored in the second intracellular compartment, the vacuole. [ 81 ]  The requirement for Mg 2+  in mitochondria has been demonstrated in yeast [ 82 ]  and it seems highly likely that the same will apply in plants. The chloroplasts also require significant amounts of internal Mg 2+ , and low concentrations of cytoplasmic Mg 2+ . [ 83 ] [ 84 ]  In addition, it seems likely that the other subcellular organelles (e.g., Golgi, endoplasmic reticulum, etc.) also require Mg 2+ .


Once in the cytoplasmic space of root cells Mg 2+ , along with the other cations, is probably transported radially into the stele and the vascular tissue. [ 85 ]  From the cells surrounding the xylem the ions are released or pumped into the xylem and carried up through the plant. In the case of Mg 2+ , which is highly mobile in both the xylem and phloem, [ 86 ]  the ions will be transported to the top of the plant and back down again in a continuous cycle of replenishment. Hence, uptake and release from vascular cells is probably a key part of whole plant Mg 2+  homeostasis. Figure 1 shows how few processes have been connected to their molecular mechanisms (only vacuolar uptake has been associated with a transport protein, AtMHX).


The diagram shows a schematic of a plant and the putative processes of Mg 2+  transport at the root and leaf where Mg 2+  is loaded and unloaded from the vascular tissues. [ 4 ]  Mg 2+  is taken up into the root cell wall space (1) and interacts with the negative charges associated with the cell walls and membranes. Mg 2+  may be taken up into cells immediately (symplastic pathway) or may travel as far as the Casparian band (4) before being absorbed into cells (apoplastic pathway; 2). The concentration of Mg 2+  in the root cells is probably buffered by storage in root cell vacuoles (3). Note that cells in the root tip do not contain vacuoles. Once in the root cell cytoplasm, Mg 2+  travels toward the centre of the root by  plasmodesmata , where it is loaded into the xylem (5) for transport to the upper parts of the plant. When the Mg 2+  reaches the leaves it is unloaded from the xylem into cells (6) and again is buffered in vacuoles (7). Whether cycling of Mg 2+  into the phloem occurs via general cells in the leaf (8) or directly from xylem to phloem via  transfer cells  (9) is unknown. Mg 2+  may return to the roots in the phloem sap.


When a Mg 2+  ion has been absorbed by a cell requiring it for metabolic processes, it is generally assumed that the ion stays in that cell for as long as the cell is active. [ 4 ]  In vascular cells, this is not always the case; in times of plenty, Mg 2+  is stored in the vacuole, takes no part in the day-to-day metabolic processes of the cell (Stelzer  et al. , 1990), and is released at need. But for most cells it is death by senescence or injury that releases Mg 2+  and many of the other ionic constituents, recycling them into healthy parts of the plant. In addition, when Mg 2+  in the environment is limiting, some species are able to mobilise Mg 2+  from older tissues. [ 78 ]  These processes involve the release of Mg 2+  from its bound and stored states and its transport back into the vascular tissue, where it can be distributed to the rest of the plant. In times of growth and development, Mg 2+  is also remobilised within the plant as source and sink relationships change. [ 4 ]


The homeostasis of Mg 2+  within single plant cells is maintained by processes occurring at the plasma membrane and at the vacuole membrane (see Figure 2). The major driving force for the translocation of ions in plant cells is ΔpH. [ 87 ]   H + -ATPases  pump H +  ions against their concentration gradient to maintain the pH differential that can be used for the transport of other ions and molecules. H +  ions are pumped out of the cytoplasm into the extracellular space or into the vacuole. The entry of Mg 2+  into cells may occur through one of two pathways, via channels using the ΔΨ (negative inside) across this membrane or by  symport  with H +  ions. To transport the Mg 2+  ion into the vacuole requires a Mg 2+ /H +   antiport  transporter (such as AtMHX). The H + -ATPases are dependent on Mg 2+  (bound to ATP) for activity, so that Mg 2+  is required to maintain its own homeostasis.


A schematic of a plant cell is shown including the four major compartments currently recognised as interacting with Mg 2+ .  H + -ATPases  maintain a constant ΔpH across the plasma membrane and the vacuole membrane. Mg 2+  is transported into the vacuole using the energy of ΔpH (in  A. thaliana  by AtMHX). Transport of Mg 2+  into cells may use either the negative ΔΨ or the ΔpH. The transport of Mg 2+  into mitochondria probably uses ΔΨ as in the mitochondria of yeast, and it is likely that  chloroplasts  take Mg 2+  by a similar system. The mechanism and the molecular basis for the release of Mg 2+  from vacuoles and from the cell is not known. Likewise, the light-regulated Mg 2+  concentration changes in chloroplasts are not fully understood, but do require the transport of H +  ions across the  thylakoid  membrane.


Mg 2+  is the coordinating metal ion in the chlorophyll molecule, and in plants where the ion is in high supply about 6% of the total Mg 2+  is bound to chlorophyll. [ 4 ] [ 88 ] [ 89 ]  Thylakoid stacking is stabilised by Mg 2+  and is important for the efficiency of photosynthesis, allowing phase transitions to occur. [ 90 ]


Mg 2+  is probably taken up into chloroplasts to the greatest extent during the light-induced development from proplastid to chloroplast or etioplast to chloroplast. At these times, the synthesis of chlorophyll and the biogenesis of the thylakoid membrane stacks absolutely require the divalent cation. [ 91 ] [ 92 ]


Whether Mg 2+  is able to move into and out of chloroplasts after this initial developmental phase has been the subject of several conflicting reports. Deshaies  et al.  (1984) found that Mg 2+  did move in and out of isolated chloroplasts from young pea plants, [ 93 ]  but Gupta and Berkowitz (1989) were unable to reproduce the result using older spinach chloroplasts. [ 94 ]  Deshaies  et al.  had stated in their paper that older pea chloroplasts showed less significant changes in Mg 2+  content than those used to form their conclusions. The relative proportion of immature chloroplasts present in the preparations may explain these observations.


The metabolic state of the chloroplast changes considerably between night and day. During the day, the chloroplast is actively harvesting the energy of light and converting it into chemical energy. The activation of the metabolic pathways involved comes from the changes in the chemical nature of the stroma on the addition of light. H +  is pumped out of the stroma (into both the cytoplasm and the lumen) leading to an alkaline pH. [ 95 ] [ 96 ]  Mg 2+  (along with K + ) is released from the lumen into the stroma, in an electroneutralisation process to balance the flow of H + . [ 97 ] [ 98 ] [ 99 ] [ 100 ]  Finally, thiol groups on enzymes are reduced by a change in the redox state of the stroma. [ 101 ]  Examples of enzymes activated in response to these changes are fructose 1,6-bisphosphatase, sedoheptulose bisphosphatase and  ribulose-1,5-bisphosphate carboxylase . [ 4 ] [ 59 ] [ 101 ]  During the dark period, if these enzymes were active a wasteful cycling of products and substrates would occur.


Two major classes of the enzymes that interact with Mg 2+  in the stroma during the light phase can be identified. [ 59 ]  Firstly, enzymes in the glycolytic pathway most often interact with two atoms of Mg 2+ . The first atom is as an allosteric modulator of the enzymes' activity, while the second forms part of the active site and is directly involved in the catalytic reaction. The second class of enzymes includes those where the Mg 2+  is complexed to nucleotide di- and tri-phosphates (ADP and ATP), and the chemical change involves phosphoryl transfer. Mg 2+  may also serve in a structural maintenance role in these enzymes (e.g., enolase).


Plant stress responses can be observed in plants that are under- or over-supplied with Mg 2+ . The first observable signs of Mg 2+  stress in plants for both starvation and toxicity is a depression of the rate of photosynthesis, it is presumed because of the strong relationships between Mg 2+  and chloroplasts/chlorophyll. In pine trees, even before the visible appearance of yellowing and necrotic spots, the photosynthetic efficiency of the needles drops markedly. [ 78 ]  In Mg 2+  deficiency, reported secondary effects include carbohydrate immobility, loss of RNA transcription and loss of protein synthesis. [ 102 ]  However, due to the mobility of Mg 2+  within the plant, the deficiency phenotype may be present only in the older parts of the plant. For example, in Pinus radiata starved of Mg 2+ , one of the earliest identifying signs is the  chlorosis  in the needles on the lower branches of the tree. This is because Mg 2+  has been recovered from these tissues and moved to growing (green) needles higher in the tree. [ 78 ]


A Mg 2+  deficit can be caused by the lack of the ion in the media (soil), but more commonly comes from inhibition of its uptake. [ 4 ]  Mg 2+  binds quite weakly to the negatively charged groups in the root cell walls, so that excesses of other cations such as K + , NH 4 + , Ca 2+ , and Mn 2+  can all impede uptake.(Kurvits and Kirkby, 1980; [ 79 ]  In acid soils Al 3+  is a particularly strong inhibitor of Mg 2+  uptake. [ 103 ] [ 104 ]  The inhibition by Al 3+  and Mn 2+  is more severe than can be explained by simple displacement, hence it is possible that these ions bind to the Mg 2+  uptake system directly. [ 4 ]  In bacteria and yeast, such binding by Mn 2+  has already been observed. Stress responses in the plant develop as cellular processes halt due to a lack of Mg 2+  (e.g. maintenance of ΔpH across the plasma and vacuole membranes). In Mg 2+ -starved plants under low light conditions, the percentage of Mg 2+  bound to chlorophyll has been recorded at 50%. [ 105 ]  Presumably, this imbalance has detrimental effects on other cellular processes.


Mg 2+  toxicity stress is more difficult to develop. When Mg 2+  is plentiful, in general the plants take up the ion and store it (Stelzer  et al. , 1990). However, if this is followed by drought then ionic concentrations within the cell can increase dramatically. High cytoplasmic Mg 2+  concentrations block a K +  channel in the inner envelope membrane of the chloroplast, in turn inhibiting the removal of H +  ions from the chloroplast stroma. This leads to an acidification of the stroma that inactivates key enzymes in  carbon fixation , which all leads to the production of oxygen  free radicals  in the chloroplast that then cause oxidative damage. [ 106 ]


Magnesium "oil"  (also referred to as  transdermal magnesium, magnesium hexahydrate ) is a colloquial misnomer for a concentrated solution of  magnesium chloride  in water. It is oily only in the sense that it feels oily to the touch, but unlike a true oil it mixes freely with water—as it must, being an aqueous solution. Magnesium oil is supposed to be applied to the skin as an alternative to taking a magnesium supplement by mouth, [ 1 ]  although it is ineffective and scientifically unsupported due to lack of any convincing data that magnesium is absorbed in significant amounts through the skin. [ 2 ] [ 3 ]


This  inorganic   compound –related article is a  stub . You can help Wikipedia by  expanding it .


Magnesium transporters  are  proteins  that transport magnesium across the  cell membrane . All forms of life require  magnesium , yet the molecular mechanisms of Mg 2+  uptake from the environment and the distribution of this vital element within the organism are only slowly being elucidated.


The ATPase function of MgtA is highly  cardiolipin  dependent and has been shown to detect free magnesium in the μM range  [ 1 ]


In bacteria, Mg 2+  is probably mainly supplied by  the CorA protein [ 2 ]  and, where the CorA protein is absent, by the  MgtE protein . [ 3 ] [ 4 ]  In yeast the initial uptake is via the Alr1p and Alr2p proteins, [ 5 ]  but at this stage the only internal Mg 2+  distributing protein identified is Mrs2p. [ 6 ]  Within the protozoa only one Mg 2+  transporter (XntAp) has been identified. [ 7 ]  In metazoa, Mrs2p [ 8 ]  and MgtE homologues [ 9 ]  have been identified, along with two novel Mg 2+  transport systems TRPM6/TRPM7 [ 10 ] [ 11 ]  and PCLN-1. [ 12 ]  Finally, in plants, a family of Mrs2p homologues has been identified [ 13 ] [ 14 ]  along with another novel protein, AtMHX. [ 15 ]


The evolution of Mg 2+  transport appears to have been rather complicated. Proteins apparently based on MgtE are present in bacteria and metazoa, but are missing in fungi and plants, whilst proteins apparently related to CorA are present in all of these groups. The two active transport transporters present in bacteria, MgtA and MgtB, do not appear to have any homologies in higher organisms. There are also Mg 2+  transport systems that are found only in the higher organisms.


There are a large number of proteins yet to be identified that transport Mg 2+ . Even in the best studied eukaryote, yeast, Borrelly [ 16 ]  has reported a Mg 2+ /H +  exchanger without an associated protein, which is probably localised to the Golgi. At least one other major Mg 2+  transporter in yeast is still unaccounted for, the one affecting Mg 2+  transport in and out of the yeast vacuole. In higher, multicellular organisms, it seems that many Mg 2+  transporting proteins await discovery.


The CorA-domain-containing Mg 2+  transporters (CorA, Alr-like and Mrs2-like) have a similar but not identical array of affinities for divalent cations. In fact, this observation can be extended to all of the Mg 2+  transporters identified so far. This similarity suggests that the basic properties of Mg 2+  strongly influence the possible mechanisms of recognition and transport. However, this observation also suggests that using other metal ions as tracers for Mg 2+  uptake will not necessarily produce results comparable to the transporter's ability to transport Mg 2+ . Ideally, Mg 2+  should be measured directly. [ 17 ]


Since  28 Mg 2+  is practically unobtainable, much of the old data will need to be reinterpreted with new tools for measuring Mg 2+  transport, if different transporters are to be compared directly. The pioneering work of Kolisek [ 18 ]  and Froschauer [ 19 ]  using mag-fura 2 has shown that free Mg 2+  can be reliably measured  in vivo  in some systems. By returning to the analysis of CorA with this new tool, we have gained an important baseline for the analysis of new Mg 2+  transport systems as they are discovered. However, it is important that the amount of transporter present in the membrane is accurately determined if comparisons of transport capability are to be made. This bacterial system might also be able to provide some utility for the analysis of eukaryotic Mg 2+  transport proteins, but differences in biological systems of prokaryotes and eukaryotes will have to be considered in any experiment.


Comparing the functions of the characterised Mg 2+  transport proteins is currently almost impossible, even though the proteins have been investigated in different biological systems using different methodologies and technologies. Finding a system where all the proteins can be compared directly would be a major advance. If the proteins could be shown to be functional in bacteria ( S. typhimurium ), then a combination of the techniques of mag-fura 2, quantification of protein in the envelope membrane, and structure of the proteins (X-ray crystal or cryo-TEM) might allow the determination of the basic mechanisms involved in the recognition and transport of the Mg 2+  ion. However, perhaps the best advance would be the development of methods allowing the measurement of the protein's function in the patch-clamp system using artificial membranes.


In 1968, Lusk [ 20 ]  described the limitation of bacterial ( Escherichia coli ) growth on Mg 2+ -poor media, suggesting that bacteria required Mg 2+  and were likely to actively take this ion from the environment. The following year, the same group [ 21 ]  and another group, Silver, [ 22 ]  independently described the uptake and efflux of Mg 2+  in metabolically active  E. coli  cells using  28 Mg 2+ . By the end of 1971, two papers had been published describing the interference of Co 2+ , Ni 2+  and Mn 2+  on the transport of Mg 2+  in  E. coli [ 23 ]  and in Aerobacter aerogenes and Bacillus megaterium. [ 24 ]  In the last major development before the cloning of the genes encoding the transporters, it was discovered that there was a second Mg 2+  uptake system that showed similar affinity and transport kinetics to the first system, but had a different range of sensitivities to interfering cations. This system was also repressible by high extracellular concentrations of Mg 2+
. [ 25 ] [ 26 ]


The CorA gene and its corresponding protein are the most exhaustively studied Mg 2+  transport system in any organism. Most of the published literature on the CorA gene comes from the laboratory of M. E. Maguire. Recently the group of R. J. Schweyen made a significant impact on the understanding of Mg 2+  transport by CorA. The gene was originally named after the cobalt-resistant phenotype in  E. coli  that was caused by the gene's inactivation. [ 25 ]


The gene was genetically identified in  E. coli  by Park  et al. , [ 26 ]  but wasn't cloned until Hmiel  et al. [ 2 ]  isolated the  Salmonella enterica  serovar Typhimurium ( S. typhimurium ) homologue. Later it would be shown by Smith and Maguire [ 27 ]  that the CorA gene was present in 17 gram-negative bacteria. With the large number of complete genome sequences now available for prokaryotes, CorA has been shown to be virtually ubiquitous among the Eubacteria, as well as being widely distributed among the Archaea. [ 28 ]  The CorA locus in  E. coli  contains a single open reading frame of 948 nucleotides, producing a protein of 316 amino acids. This protein is well conserved amongst the Eubacteria and Archaea. Between  E. coli  and  S. typhimurium , the proteins are 98% identical, but in more distantly related species, the similarity falls to between 15 and 20%. [ 28 ]  In the more distantly related genes, the similarity is often restricted to the C-terminal part of the protein, and a short amino acid motif GMN within this region is very highly conserved. The CorA domain, also known as PF01544 in the pFAM conserved protein domain database ( http://webarchive.loc.gov/all/20110506030957/http%3A//pfam.sanger.ac.uk/ ), is additionally present in a wide range of higher organisms, and these transporters will be reviewed below.


The CorA gene is constitutively expressed in  S. typhimurium  under a wide range of external Mg 2+  concentrations. [ 29 ]  However, recent evidence suggests that the activity of the protein may be regulated by the PhoPQ  two-component regulatory system . [ 30 ]  This sensor responds to low external Mg 2+  concentrations during the infection process of  S. typhimurium  in humans. [ 31 ]  In low external Mg 2+  conditions, the PhoPQ system was reported to suppress the function of CorA and it has been previously shown that the transcription of the alternative Mg 2+  transporters MgtA and MgtB is activated in these conditions. [ 29 ]  Chamnongpol and Groisman suggest that this allows the bacteria to escape metal ion toxicity caused by the transport of other ions, particularly Fe(II), by CorA in the absence of Mg 2+ . [ 30 ]  Papp and Maguire offer a conflicting report on the source of the toxicity. [ 32 ]


The figure (not to scale) shows the originally published transmembrane (TM) domain topology of the  S. typhimurium  CorA protein, which was said to have three membrane-spanning regions in the C-terminal part of the protein (shown in blue), as determined by Smith  et al. . [ 33 ]  Evidence for CorA acting as a homotetramer was published by Warren  et al.  in 2004. [ 34 ]  In December 2005 the crystal structure of the CorA channel was posted to the RSCB protein structure database. The results showed that the protein has two TM domains and exists as a homopentamer, in direct conflict with the earlier reports.  Follow this link to see the structure in 3D . The soluble intracellular parts of the protein are highly charged, containing 31 positively charged and 53 negatively charged residues. Conversely, the TM domains contain only one charged amino acid, which has been shown to be unimportant in the activity of the transporter. [ 35 ]  From mutagenesis experiments, it appears that the chemistry of the Mg 2+  transport relies on the hydroxyl groups lining the inside of the transport pore; there is also an absolute requirement for the GMN motif (shown in red). [ 35 ] [ 36 ]


Before the activity of CorA could be studied  in vivo , any other Mg 2+  transport systems in the bacterial host had to be identified and inactivated or deleted (see below). A strain of  S. typhimurium  containing a functional CorA gene but lacking MgtA and MgtB was constructed [ 37 ] (also see below), and the uptake kinetics of the transporter were analysed. [ 38 ]  This strain showed nearly normal growth rates on standard media (50 μM Mg 2+ ), but the removal of all three genes created a bacterial strain requiring 100 mM external Mg 2+  for normal growth. [ 37 ]


Mg 2+  is transported into cells containing only the CorA transport system with similar kinetics and cation sensitivities as the Mg 2+  uptake described in the earlier papers, and has additionally been quantified [ 38 ] (see table). The uptake of Mg 2+  was seen to plateau as in earlier studies, and although no actual mechanism for the decrease in transport has been determined, so it has been assumed that the protein is inactivated. [ 19 ]  Co 2+  and Ni 2+  are toxic to  S. typhimurium  cells containing a functional CorA protein and this toxicity stems from the blocking of Mg 2+  uptake (competitive inhibition) and the accumulation of these ions inside the cell. [ 2 ]  Co 2+  and Ni 2+  have been shown to be transported by CorA by using radioactive tracer analysis, [ 2 ] [ 39 ]  although with lower affinities (km) and velocities (Vmax) than for Mg 2+  (see table). The km values for Co 2+  and Ni 2+  are significantly above those expected to be encountered by the cells in their normal environment, so it is unlikely that the CorA transport system mediates the uptake of these ions under natural conditions. [ 2 ]  To date, the evidence for Mn 2+  transport by CorA is limited to  E. coli . [ 26 ]


The table lists the transport kinetics of the CorA Mg 2+  transport system. This table has been compiled from the publications of Snavely  et al.  (1989b), [ 38 ]  Gibson  et al.  (1991) [ 39 ]  and Smith  et al.  (1998a) [ 35 ]  and summarises the kinetic data for the CorA transport protein expressed from the wild type promoter in bacteria lacking MgtA and MgtB. km and Vmax were determined at 20 °C as the uptake of Mg 2+  at 37 °C was too rapid to measure accurately.