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Manganese metabolism in humans

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Abstract

Manganese (Mn) is an essential nutrient for intracellular activities; it functions as a cofactor for a variety of enzymes, including arginase, glutamine synthetase (GS), pyruvate carboxylase and Mn superoxide dismutase (Mn-SOD). Through these metalloproteins, Mn plays critically important roles in development, digestion, reproduction, antioxidant defense, energy production, immune response and regulation of neuronal activities. Mn deficiency is rare. In contrast Mn poisoning may be encountered upon overexposure to this metal. Excessive Mn tends to accumulate in the liver, pancreas, bone, kidney and brain, with the latter being the major target of Mn intoxication. Hepatic cirrhosis, polycythemia, hypermanganesemia, dystonia and Parkinsonism-like symptoms have been reported in patients with Mn poisoning. In recent years, Mn has come to the forefront of environmental concerns due to its neurotoxicity. Molecular mechanisms of Mn toxicity include oxidative stress, mitochondrial dysfunction, protein misfolding, endoplasmic reticulum (ER) stress, autophagy dysregulation, apoptosis, and disruption of other metal homeostasis. The mechanisms of Mn homeostasis are not fully understood. Here, we will address recent progress in Mn absorption, distribution and elimination across different tissues, as well as the intracellular regulation of Mn homeostasis in cells. We will conclude with recommendations for future research areas on Mn metabolism.
1655
defense, energy production, immune response and
regulation of neuronal activities. Mn deciency is
rare. In contrast Mn poisoning may be encountered
upon overexposure to this metal. Excessive Mn tends
to accumulate in the liver, pancreas, bone, kidney
and brain, with the latter being the major target of
Mn intoxication. Hepatic cirrhosis, polycythemia,
[Frontiers In Bioscience, Landmark, 23, 1655-1679, March 1, 2018]
Manganese metabolism in humans
Pan Chen1, Julia Bornhorst2, Michael Aschner1
1Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, 2Department
of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany D-14558
TABLE OF CONTENTS
1. Abstract
2. Introduction
3. Mn absorption and distribution in humans
3.1. exposure routes and absorption
3.1.1. Ingestion
3.1.2. In utero exposure
3.1.3. Inhalation
3.1.4. Intravenous administration and dermal exposure
3.2. Distribution and regulation
3.2.1. Blood
3.2.2. Liver
3.2.3. Bone
3.2.4. Pancreas
3.2.5. Kidney
3.2.6. Brain
3.3. Elimination
4. Mn metabolism regulated by Mn transporters at the cellular level
4.1. Transported Mn-species
4.2. Membrane Mn transporters
4.2.1. Mn inux: TfR, DMT1, ZIP8/ZIP14, calcium channels, citrate transporter, DAT,
choline transporter, ceruloplasmin
4.2.2. Mn efux: Ferroportin, SLC30A10, NCX
4.3. Intracellular Mn transporters
4.3.1. Endosome: TfR and DMT1
4.3.2. Lysosome: PARK9/ATP13A2
4.3.3. Golgi: SPCA1, HIP14, SLC30A10 and Ca channels
4.3.4. Mitochondria: DMT1, TfR, citrate transporter and Ca uniporter
4.3.5. Nucleus: unknown
5. Summary and future directions
6. Acknowledgement
7. References
1. ABSTRACT
Manganese (Mn) is an essential nutrient for
intracellular activities; it functions as a cofactor for a
variety of enzymes, including arginase, glutamine
synthetase (GS), pyruvate carboxylase and Mn
superoxide dismutase (Mn-SOD). Through these
metalloproteins, Mn plays critically important roles
in development, digestion, reproduction, antioxidant
Role of manganese in humans
1656 © 1996-2018
and legumes contain the highest levels of Mn, leafy
green vegetables, tea, chocolate and seafood (clams
and mussels) are also abundant in Mn. Multivitamins
and other daily supplements also contain Mn, although
the levels vary.
Although Mn is required for various physiological
activities, accumulation of excessive Mn in human body
can result in severe toxicity. The primary target tissue
of Mn toxicity is the brain, and “manganism” refers to a
variety of psychiatric and motor disturbances caused by
excessive Mn accumulation. Reduced response speed,
irritability, mood changes and compulsive behaviors are
rst noticed in the patients (6); later on, the symptoms
get more prominent with four-limb dystonia, an upright
stance, tremors at rest and a signature high-stepping
gait (7, 8). These symptoms resemble, however, are not
identical to symptoms of idiopathic Parkinson’s disease
(PD) (9). Mn preferentially accumulates in the globus
pallidus. Although dopaminergic (DAergic) neurons in
the substantia nigra pars compacta (SNpc) are affected
by excess Mn, the effect is not as prominent as in PD
patients, and loss of DAergic neurons is not as common
as in PD. In addition, patients with manganism do not
respond to levodopa therapy as well as PD patients (10).
Other than neurological symptoms, liver impairments
are found in most patients, with micronodular
cirrhosis, elevated transaminases and unconjugated
hyperbilirubinemia (8). Mn overexposure can also
impair cardiovascular function, causing abnormal
electrocardiogram, increased heartbeat, shorter P-R
interval and lower diastolic blood pressure (11).
3. MN ABSORPTION AND DISTRIBUTION IN
HUMANS
Manganese is absorbed by ingestion,
inhalation and dermal permeation, and also
administered in intravenous injection. It is rapidly
absorbed in the gastrointestinal (GI) tract and in the
lung, then distributed into different tissues through blood
circulation. Liver, pancreas, bone, kidney and brain are
the organs containing the highest Mn levels in human
body. It has to be claried that Mn level in the brain
is not the highest among these organs, however, the
brain is the major target of Mn-induced toxicity as most
of the patients with Mn intoxication show symptoms of
neurological dysfunction. Thus how Mn crosses the
blood-brain barrier (BBB) and accumulates in the brain
is of special interest. We will review the processes of
Mn uptake, distribution and elimination, as well as the
factors that regulate these processes.
3.1. Exposure routes and absorption
3.1.1. Ingestion
Oral exposure is the most common route for
Mn absorption. Drinking water, Mn-rich vegetables,
hypermanganesemia, dystonia and Parkinsonism-
like symptoms have been reported in patients with
Mn poisoning. In recent years, Mn has come to
the forefront of environmental concerns due to its
neurotoxicity. Molecular mechanisms of Mn toxicity
include oxidative stress, mitochondrial dysfunction,
protein misfolding, endoplasmic reticulum (ER) stress,
autophagy dysregulation, apoptosis, and disruption
of other metal homeostasis. The mechanisms of Mn
homeostasis are not fully understood. Here, we will
address recent progress in Mn absorption, distribution
and elimination across different tissues, as well as
the intracellular regulation of Mn homeostasis in cells.
We will conclude with recommendations for future
research areas on Mn metabolism.
2. INTRODUCTION
Mn is the 12th most abundant element and
5th most abundant metal on the earth. This metal has
a silver-grey color and is very easy to oxidize. Thus,
Mn is not found as a free element, but usually exists as
oxides, carbonates and silicates. The naturally occurring
and most stable isotope is 55Mn, and 18 radioisotopes
have been discovered, with a half-life from seconds to
million years. Although found in a negative oxidation
state (-3), Mn commonly exists in positive oxidation
states (+2, +3, +4, +6, and +7). In living organisms,
the most commonly oxidized states are Mn2+ and Mn3+.
Mn2+ is the most stable form, while Mn3+ is a powerful
oxidant, which is usually disproportionated to Mn2+
and Mn4+, or forms complexes with proteins, such as
transferrin (Tf) (1). Natural earth erosion releases tons
of Mn into the air, soil and waterways on an annual
basis, which is subsequently available for absorption by
microorganisms, plants and animals. Given its physical
and chemical properties, Mn is widely used in various
industrial settings. In manufacture, Mn is incorporated
in production of batteries, ceramics, steel, cosmetics,
leather, reworks and glass. In energy consumption,
the combustion of gas releases Mn phosphate
into the atmosphere secondary to the usage of an
antiknock gasoline additive - methylcyclopentadienyl
Mn tricarbonyl (MMT). In agriculture, Mn is present
in various pesticides and fungicides, such as Maneb
and Mancozeb, which may result in adverse health
effect in farmers and others. In medicine, given its
paramangnetic property, Mn serves as a contrast agent
in medical magnetic resonance imaging (MRI) (2, 3).In
the infant food industry, Mn is commonly added to total
parenteral nutrition (TPN) at signicant concentrations
as an essential nutrient (4).
Dietary consumption is the primary route
of Mn intake for majority of people. Drinking water
contains Mn levels ranging from 1mg/L up to 2 mg/L
depending on the locations and contamination (5). In
human daily diets, rice, nuts (hazelnuts, almonds, and
pecans), whole grains (wheat germ, oats, and bran)
Role of manganese in humans
1657 © 1996-2018
levels in the brain is upregulated in iron-decient rats
(24) and pigs (25). Approximately 75% of human milk
Mn is bound to lactoferrin (26), and the absorption of
this complexed Mn could be inhibited by excess ferric
lactoferrin in the brush-border membrane vesicles from
the small intestine of infant monkey (27). Furthermore,
addition of Ca to human milk signicantly decreased
Mn absorption in both male and female adults; in
contrast, addition of phytate, phosphate and ascorbic
acid to infant formula, as well as iron and magnesium to
wheat bread had no signicant effect on Mn absorption
(28). In rats, when complexed with albumin or albumin-
like proteins, Mn tends to discharge from the intestine,
but the transferrin complexed or carrier-free Mn does
not (29). Age is another factor known to inuence Mn
absorption. Infants and children tend to absorb higher
amount of Mn from diet due to a large demand of Mn in
body development compared with adults. In neonatal
rats fed with human milk, bovine milk or infant formula,
the absorption of Mn from these milk diets decreased
signicantly with age (30). Moreover, the Mn retention
rate (80%) in rat pups (<15 days) was much higher
than in older pups (40%) or adults (31). Although most
of Mn uptake is through ingestion, it is considered
relatively safe due to efcient liver elimination.
3.1.2. In utero exposure
In utero Mn exposure is often neglected as
the direct link between Mn exposure and health effects
is obscure. However, there has been an increasing
number of studies correlating in utero Mn exposure
and infant health. Average Mn concentration (78.7.5
mg/L) in umbilical cord blood is higher than in the
mother’s whole blood (54.9.8 mg/L) and an inverted
U-shaped curve has been noted between mothers’
whole blood Mn levels and birth weights, as well as
between umbilical blood Mn levels and birth weights
(32). Similar results were observed in other studies (33-
35), indicating both low and high maternal blood Mn
levels were associated with impaired infant health.
3.1.3. Inhalation
Most of clinically reported cases of Mn
intoxication are due to occupational exposure.
Inhalation of airborne Mn is the major exposure route
in occupational Mn intoxication. Industrial workers,
especially miners (36), smelters (37) and welders (38),
breathe in a signicant amount of Mn-containing fume
and dust, thus are the adult population with the highest
risk for Mn-induced toxicity. Inhaled Mn is absorbed in
the lung and enters the circulation. It can be rapidly
transported to the olfactory bulb and enter the brain
by two Zinc transporters ZIP8 and ZIP14, bypassing
the liver and BBB (9). In rats exposed to 0.0.92 mg
MnSO4/m3, the level of Mn in the lung was elevated;
at 0.9.2 mg MnSO4/m3, Mn concentrations in the lung,
striatum and bile were signicantly increased (39).
nuts, vitamins, supplements and infant formula are the
major Mn food source. In adults, approximately 3-5%
of ingested Mn is absorbed through the gastrointestinal
(GI) tract, and females tend to have a higher absorption
rate (3.5.5 ± 2.1.1%, ~2.3. mg/day) than males (1.3.5
± 0.5.1%, ~1.8. mg/day), which is possibly affected by
iron status (4, 12, 13). The average intake of Mn is
2.3. to 8.8. mg per day in western diets (14). Currently,
the formal recommended dietary allowance for Mn
has not been established yet, but the estimated safe
and adequate daily dietary intake of Mn for adults is
2–5 mg per day, and the lowest Mn level in water with
observable adverse effect is 4.2. mg per day for a 70-
kg individual (15). However, the number can be much
higher in infants or children, due to a higher demand
for Mn and a less developed regulatory system at early
developmental stages. A daily consumption of 3 mg Mn
is sufciently for an infant up to 6 months of age, and a
daily intake of 1.2. and 1.5. mg is adequate for children
of 1-3 years old and 4-8 years old, respectively (13).
The World Health Organization (WHO) recommends
Mn concentration in drinking water < 400 mg/L (16).
In the US the human health benchmark is set at 300
mg/L (17). In contrast, in Bangladesh the level may
be as high as 2 mg/L in the water supply (5), a level
which is associated with altered classroom behavior
in school-aged (8 to 11 years old) children (18). Infant
formula especially soy-based formula is another Mn
food source that may result in Mn accumulation in
infants (19, 20). However, it can be as 10-fold higher
than the recommended level due to lack of maximum
requirement of Mn levels in formula production (14).
Ingested Mn is rapidly absorbed in the
intestine, where it enters cells through passive
diffusion or active transport. In human intestinal cells,
Mn is transported in a biphasic pattern with a saturable
process similar to other divalent cations, such as
iron and calcium (21). It takes about one hour to
activate the cellular components (mainly transporters),
followed by a progressive acceleration of Mn uptake
after a steady-state condition (21). In rat intestinal
cells, a high afnity, low capacity, active transport
mechanism is reported to regulate Mn absorption (22).
The divalent metal transporter 1 (DMT1) is considered
to be mainly responsible for active Mn inux, although
it also transports other divalent cations. Several
factors regulate the absorption of Mn. Mn importers
are not necessarily Mn-specic transporters, as they
also regulate inux of other metals, such as iron (Fe),
copper (Cu), zinc (Zn), calcium (Ca), etc. Therefore,
the presence of other metals in the biological media
(blood, extracellular uid, etc) will compete with Mn
absorption.
Individuals with Fe deciency are at higher
risk of Mn poisoning as Mn absorption in the GI tract
can increase under low Fe conditions (23). Similarly,
the expression of Fe/Mn transporters is altered and Mn
Role of manganese in humans
1658 © 1996-2018
complex (49-51). Mn3+ is a highly reactive oxidant
and usually gets reduced to Mn2+. Interestingly, Mn2+
can be oxidized to Mn3+ by ceruloplasmin, which is
an abundant plasma protein synthesized in the liver
and able to oxidize iron and copper (52). In mice,
ceruloplasmin has been shown to regulate Mn levels
in the blood and kidney, as well as the brain and lung to
a lesser extent; meanwhile, this protein also elevates
brain oxidative stress probably via an extracellular
ceruloplasmin—manganese redox mechanism upon
chronic Mn exposure (52). Transferrin is also produced
in the liver and secreted in the plasma. This circulating
protein binds to both Mn2+ and Mn3+; together with
transferrin receptor (TfR), Tf regulates Mn3+ transport
to the brain in a way similar to Tf/Fe3+ transport, but
this process is less efcient compared with other
transporter mediated Mn transport processes (53).
3.2.2. Liver
Liver is the primary organ to regulate body
Mn levels through endogenous gut losses of Mn (29).
The liver cells express various Mn transporter on
the cell membrane, including DMT1 (54), transferrin/
transferrin receptor (Tf/TfR) (55, 56), ZIP14 (54, 57)
and citrate transporters (58), which regulate Mn inux.
Meanwhile, Mn exporters including SLC30A10 (59),
ferroportin (60) and SPCA1 (61) are also expressed
in the liver, regulating efux of excess Mn. Thus, liver
plays an important role in Mn storage, redistribution
and elimination. As the blood passes through the
liver, a small but adequate amount of Mn required for
physiological functions remains in the plasma, while
excess Mn is sequestered by liver cells and conjugated
to bile, which then passed to the intestine and excreted
in the feces (29, 62).
3.2.3. Bone
Bone is another tissue with extensive Mn
accumulation with a normal concentration of 1 mg/kg
(14, 63) and approximately 40% total body Mn (62).
Thus, bone Mn can be used as a biomarker for Mn
exposure. Using in vivo neutron activation analysis
(IVNAA) bone Mn measurements, Pejović‐Milić and
colleagues found that the mean Mn level (2.9.±0.4.
mg Mn/g Ca) in the hand bone of welders exposed
to Mn rich environment, was signicantly higher than
the non-occupationally exposed subjects (0.1.±0.7.
mg Mn/g Ca) (64). In adult rats, atomic absorption
spectrometry (AAS) revealed that Mn concentrations
in bone reached a steady state after 6-week of Mn
exposure, with approximately 2-3 fold increase of
bone Mn levels before exposure (65). The half-life of
Mn in femur, tibia and humerus bones was 77, 263
and 429 days, respectively; the average half-life of rat
skeleton bone was 143 days, which was about 8.5.
years in human (65). In addition, Mn concentrations in
striatum, hippocampus and cerebrospinal uid (CSF)
3.1.4. Intravenous administration and dermal
exposure
Intravenous administration of agents containing
high levels of Mn is another Mn exposure route, which
bypasses the regulation at the GI tract resulting
in 100% absorption of the metal (4). For example,
premature infants fail to absorb sufcient amounts of
nutrients due to an undeveloped GI tract or certain
diseases. Thus, they are commonly supplemented with
total parenteral nutrition (TPN) by intravenous injection,
which contains many trace elements required for life
support. Infants taking TPN are of special concern
of Mn poisoning. In addition, intravenous abuse of
methcathinone, containing manganese dioxide as a
byproduct of synthesis, has been reported to result in
manganism (40-43). The absorbed amount can reach
from 60 to 180 mg per day, far beyond the average
intake from diet (41-43). Furthermore, Mn exposure
through skin is also a risk factor for individuals with
contact to organic forms of Mn, such as the gasoline
supplement methylcyclopentadienyl manganese
tricarbonyl (MMT) (2).
3.2. Distribution and regulation
In the human body, liver (1.2-1.3 mg/kg),
pancreas (1.04 mg/kg), bone (1 mg/kg), kidney (0.98
mg/kg) and brain (0.15-0.46 mg/kg) are the organs
containing highest Mn levels (44). After absorbed in
the GI tract or the lung, Mn enters the blood stream
and then quickly distributes to different tissues.
3.2.1. Blood
The normal Mn concentrations in human
blood ranges from 4 to 15 mg/L (2), and females tend
to have a ~30% higher Mn level than males (45),
probably due to a higher absorption rate in women.
Currently, the mechanism behind Mn absorption in the
intestine and delivery to the plasma remains unclear.
Most of the blood Mn (~60%) is distributed in soft
tissues, the rest is rapidly delivered to the liver (30%),
kidney (5%), pancreas (5%), colon (1%), bone (0.5.%),
urinary system (0.2.%), brain (0.1.%) and erythrocytes
(0.0.2%) (46).
Erythrocytes are responsible for Mn
distribution due to its ability to carry the Mn ion with the
presence of various Mn transporters, including DMT1
and transferrin receptor (TfR) on the cell surface (47,
48). The divalent Mn2+ and trivalent Mn3+ are the two
major Mn species in the blood, although the exact ratio
of these two species remains unknown. Mn2+ is the
predominant form in the blood and exists in complexed
with different molecules, including albumin (84%
of total Mn2+), hexahydrated ion (6%), bicarbonate
(6%), citrate (2%), and transferrin (Tf) (1%); almost
all Mn3+ is bound to transferrin to form a more stable
Role of manganese in humans
1659 © 1996-2018
their long lifespan and high energy demand. Brain Mn
can be detected by T1-weighted magnetic resonance
imaging (MRI) given the paramagnetic property of Mn
ion. In both industrial workers exposed to high levels of
Mn and individuals carrying genomic mutations without
high environmental Mn exposure, MRI studies showed
that in the brain, Mn preferentially accumulates in
the globus pallidus, followed by putamen, caudate,
midbrain, cerebellum, subthalamic and dentate
nucleus and sparing of the thalamus and ventral pons
(8, 48, 59, 71). In rats, the highest Mn intensity was
found in the globus pallidus, the thalamus and the
substantia nigra pars compacta, followed by caudate
putamen, axon bundles, and cortex (72). Mn enters
the brain via three routes: the blood-brain barrier
(BBB), the blood-cerebrospinal uid (CSF) barrier and
the olfactory tract.
Following oral uptake the BBB and the blood-
CSF barrier are the two main interfaces regulating the
brain Mn homeostasis. While the BBB separates blood
from brain interstitial uid and consists basically of
capillary endothelial cells (73), the blood-CSF barrier
is composed of epithelial cells of the choroid plexus,
which separate the blood from the CSF (74). Mn has
been shown to cross both barriers (75, 76). However
based on in vitro studies using porcine models of the
brain barriers, the blood-CSF barrier is considered
as a major route for Mn into the brain. (76). In direct
comparison with the in vitro BBB model, the blood-
CSF barrier model was much more sensitive toward
Mn illustrated by a disturbance of barrier properties.
Additionally Mn crosses the blood-CSF barrier model
site-directed, most probably by an active Mn transport
toward the brain facing compartment. The protection
afforded by the BBB and blood-CSF barrier is essential
for regulating Mn homeostasis and is essential for
neuronal survival and proper central nervous system
functioning. In this context concerns are rising about
the risk of an elevated dietary Mn exposure of infants
due to their immature BBB (77). This might contribute
to increased rates of Mn uptake and deposition in infant
brain and tissue (78). The olfactory route provides a
pathway for inhaled Mn, which comes into contact with
the olfactory epithelium, to pass directly to the brain,
thereby circumventing the two brain barriers (79).
3.3. Elimination
As mentioned above, an average of 2.3.
to 8.8. mg Mn is absorbed daily (14). However, only
2.3. mg/day required for men and 1.8. mg/day for
women (4). The extra Mn needs to be eliminated.
The turnover of ingested Mn is relatively fast, with an
average retention of 10 days (80). Most of excess Mn
is conjugated to bile by the liver and get eliminated
via fecal excretion (29, 62). Liver plays a critical role
in this process as it is reported that the liver is the
major source of endogenous gut losses of Mn (29).
was found to be relevant to bone Mn levels (65),
indicating a possible redistribution of bone Mn to the
central nervous system and a risk factor for developing
manganism.
3.2.4. Pancreas
The distribution of Mn in the pancreas and
kidney is less studied. Kodama and colleagues studied
Mn distribution in Wistar rats by subcutaneous delivery
of 15 mg of Mn/kg daily for 10 days. They found that
Mn concentration in the pancreas was signicantly
increased from 1.4. to 13.3. mg/g wet tissue, and Mn
was found in the high-molecular-mass protein fraction
(66). Interestingly, they identied that Mn bound to the
Zn binding site of protein zymogen of carboxypeptidase
B (pro-CBP), which was the primary Mn-binding protein
in the pancreas (66). In pancreatic islets isolated from
ob/ob mice incubated with 0.2.5 mM Mn for 1 hour,
the intracellular Mn concentration was about 25-fold
higher than that of the extracellular medium which
was stimulated by 20 mM D-glucose due to inhibition
of Mn efux in the islets (67). Interestingly, in Korean
diabetes patients, blood Mn concentrations were
signicantly lower than the control group, suggesting
blood Mn may regulate glucose homeostasis (68).
3.2.5. Kidney
Kidney also contains high levels of Mn. In
Korean population, people with renal dysfunction
have signicantly lower blood Mn concentrations than
the healthy group (68), indicating kidney may plays
a role in mediating blood Mn levels or vice versa. In
rats exposed to Mn by oral gavage, the kidney and
prostate glands of male rats showed the most obvious
lesions. Animals had viscous, gritty urine, and even
urinary bladder stones, and tubulointerstitial nephritis
with tubular proteineous and glomerulosclerosis was
also reported. However, female rats were affected,
indicating a sex-preference of Mn intoxication in
these rats (69). The absorption of Mn in the kidney is
regulated by several Mn transporters, including ZIP8,
ZIP14 and DMT1 in the epithelial cells of proximal
tubules in the kidney, as knockdown of these three
transporters signicantly reduced Mn uptake (70).
Mn excretion happened primarily in the apical
side of the proximal tubule cells (70) although the
mechanism has not been revealed yet.
3.2.6. Brain
The human brain is the most susceptible
organ to Mn intoxication, as neurological disorders are
the most obvious and severe symptoms seen in people
with Mn poisoning, although brain Mn levels are lower
than those in liver, pancreas, bone and kidney. Neurons
are more susceptible to Mn intoxication possibly due to
Role of manganese in humans
1660 © 1996-2018
Rats fed with Mn diet absorbed about 8% of ingested
Mn and then 37% of the absorbed Mn was excreted
through endogenous hepatobiliary elimination of Mn
(29). Therefore, individuals with hepatic problems
are at higher risk of Mn intoxication. In addition to the
primary fecal hepatobiliary elimination, Mn excretion
through urine (81), milk (82) and sweat (83) has also
been reported but with very limited amount. However,
the ratio of elimination via different routes may change
under certain circumstances. For example, when using
hexameric Mn dendrimer as a MRI contrast agent,
Mn clearance through renal routes was increased
dramatically equal to or over the amount eliminated
through hepatobiliary route (84).
4. MN METABOLISM REGULATED BY MN
TRANSPORTERS AT CELLULAR LEVEL
Mn can cross the neural barriers by means
of transporters and in different oxidation states (85).
Although Mn transporters have been vigorously
investigated, a conclusive result is presently not
available since information from different papers and
research groups are contradictory (85-87). Also the
process itself as well as the transported Mn-species
are strongly debated.
4.1. Transported Mn-species
Focusing on the transported species rst,
the three most relevant species entering the brain
are Mn2+, Mn2+/3+ citrate and Mn3+ transferrin (Mn-Tf).
Evidence from animal models, as well as human
CSF suggests that Mn-citrate is the major Mn-related
species entering the brain (88-90). Brain inux rates
have been compared in several animal studies and
pointed out to a higher rate for Mn-citrate than unbound
or protein-bound Mn (88, 90). Speciation studies
performed in human by Michalke and coworkers found
Mn from CSF correlated with Mn-Tf, the physiological
Mn carrier in serum, as long as total Mn concentration
was below 1.5. µg/l. Above 1.9. µg/L, Mn in serum
and CSF were positively correlated with Mn-citrate in
serum (89, 91, 92). Whether elevated concentrations
of Mn-citrate in serum or plasma could be a valuable
effect biomarker for increased total Mn concentration
in CSF (and brain) need to be proven in further studies.
4.2.1. Mn inux: TfR, DMT1, ZIP8/ZIP14,
calcium channels, citrate transporter, DAT,
choline transporter, ceruloplasmin
The valence status might account for the
transport properties of Mn species at the respective
barrier. Mn3+ inux from the blood into the CNS is
facilitated via Tf receptor-mediated endocytosis.
Synthesized in the liver and released to the blood,
Tf is binding Mn as a plasma-carrier (93, 94). The
TfR expressed in neurons, microglia, astrocytes and
cells of the neuronal barriers, recognizes, binds and
transports Mn into the CNS (95, 96). Intracellularly,
it is suggested that specic organelles have different
concentrations of TfR with high concentrations in the
Golgi cisternae, the plasmalemmal pits and the vesicle
membrane (97). As an early event in response of Mn
exposure an upregulation of TfR trafcking has been
observed (98, 99).
However, the majority of Mn in the body is in
the divalent oxidation state. Thereby the best studied
importer is the divalent metal transporter 1 (DMT1),
also known as divalent cation transporter 1 (DCT1),
natural resistance-associated macrophage protein
2 (NRAMP 2) or solute carrier family 11 member 2
(SLC11A2). DMT1 is reported to have a wide range
of substrates as Fe2+, Zn2+, Mn2+, Cu2+, Co2+, Cd2+, Ni2+
and Pb2+ with the following transport afnity (reecting
transport efcacy): Mn>Cd>Fe>Pb~Co~ Ni>Zn (100).
Recently, a study dened the conformational changes
underlying transition-metal ion transport in the SLC11
family, providing molecular insight to its coupling
to protons (101). DMT1 expression in the brain is
prominent in neurons, whereas studies report on
lower as well as varying protein expression in DMT1
in non-neuronal cells such as astrocytes, microglia
and oligodendrocytes, and the two principal cell types
that form the brain barriers (102). DMT1 in the brain
is highly expressed in the SN, globus pallidus (GP),
hypothalamic nucleus and striatum making them more
susceptible to Mn accumulation and toxicity (103).
DMT1 is located at cellular membranes, endosomal
membranes as well as the outer mitochondrial
membrane (104). Since the expression of DMT1 in
brain capillary endothelial cells remains debatable, it
is suggested that Mn might access the brain without
the involvement of DMT1. While some studies imply a
physiological role for the transport of Mn by DMT1 (105,
106), others suggest no direct evidence supporting its
role (76, 107). Since Mn and Fe share and compete
for Tf as well as DMT1, an altered amount of either
Fe or Mn in the brain may result in a dysregulation of
the other, causing altered homeostasis (summarized
in (108)).
Next to Fe, Mn has also been reported to
compete for transporters of other divalent metals. Mn
has also been reported to be transported by a family
of Zn transporters. Zn-interacting protein 8 (ZIP8) and
14 (ZIP14) are transmembrane proteins that belong to
the SLC39 family of genes which are expressed on the
apical surface of brain capillaries. These divalent metal/
bicarbonate ion symporters are known to transport Mn,
Zn, and Cd under normal conditions (109). ZIP8 appears
to be more important for Mn than Zn homeostasis
(110). Both ZIP8 and ZIP14 have high afnity for Mn
and ZIP8 overexpression has been shown to stimulate
intracellular accumulation of Cd and Mn (111, 112).
Since the expression of these two transporters is lower
Role of manganese in humans
1661 © 1996-2018
in the brain than in other tissues, they may be more
important in regulating body Mn levels by controlling the
absorption through the liver and lung (113). Specically,
ZIP8 is proposed to regulate Mn metabolism in the
liver, which in turn regulates Mn content in other organs
and tissues, including kidney, brain, heart and whole
blood. ZIP8, localized to the hepatocyte canalicular
membrane, functions to reclaim Mn from biliary
excretion which is supposed to be the mechanism
underlying the association of the ZIP8 locus with whole-
blood Mn and the severe Mn deciency in patients with
ZIP8 mutations (114). A study performing whole-exome
sequencing in children demonstrate that variants in ZIP8
impair the function of Mn-dependent enzymes, most
notably ß-1,4-galactosyltransferase, a Golgi enzyme
essential for biosynthesis of the carbohydrate part of
glycoproteins. SLC39A8 deciency linked for the rst
time Mn deciency with inherited glycosylation disorders.
As therapeutic step dietary galactose supplementation
is suggested to be effective (110). However, Tuschl
et al. (2016) demonstrated that ZIP14 functions as a
pivotal manganese transporter and they identied a
novel autosomal recessive disorder of Mn homeostasis
caused by homozygous mutations in ZIP14 that lead to
early-onset rapidly-progressive parkinsonism–dystonia
with distinctive brain magnetic resonance imaging
(MRI) appearances and neurodegenerative features
on post-mortem examination. Additionally the patients
show no excessive Mn in the liver, possibly due to the
bypassing of hepatic uptake by Mn and subsequent
biliary excretion in the absence of ZIP14. Next to
the ndings in patients they show that mutations in
ZIP14 impair manganese transport in vitro and lead
to manganese dyshomeostasis and altered locomotor
activity in zebrash with ZIP14 null mutations (115).
Furthermore ZIP14 KO mice exhibited
excessive Mn accumulation in the brain associated
with impaired motor function (116). Being expressed in
the nasal respiratory epithelium and olfactory receptor
neuron dendrites ZIP8 and ZIP14 might further play
a role in uptake of inhaled Mn through the olfactory
pathway, bypassing the neuronal barriers (113).
In addition, the Mg transporter HIP14 and
Ca channels located in the plasma membrane are
reported to be involved in Mn uptake, and therefore,
may play a role in Mn accumulation in the brain. Mn
has been shown to enter cell membranes trough
store-operated Ca channels which are expressed in
brain endothelial cells (117). Besides store-operated
calcium channels also voltage-gated Ca channels as
well as ionotropic glutamate receptor channels have
reported permeability to Mn (118). The expression of
voltage-gated Ca channels is higher in dopaminergic
neurons of the midbrain, which could contribute to
their selective vulnerability induced by Mn (119). Use
of a Ca channel blocker resulted in an inhibited Mn
uptake in human erythrocytes (120). Mn2+ can acutely
inhibit ATP-dependent Ca2+ signaling in astrocytes
by blocking Ca2+ entry through the receptor-operated
cation channel, TRPC3. Consequently critical
homeostatic functions necessary for metabolic and
trophic support of neurons might be comprised (121).
As already noted above, Mn-citrate is thought
to be the major Mn-related species entering the brain,
indicating citrate transporters might represent another
putative Mn transporter system. It has been suggested
that a Mn-citrate tridentate complex with a non-
coordinated central carboxylate recognition moiety
could be a substrate for the organic anion transporter
or a monocarboxylate transporter (MCT). Evidence for
an H+-dependent mechanism suggests the possibility
that MCT-1 mediates Mn-citrate uptake (75). However,
the role of citrate as an efcient in vivo Mn transport
needs to be further investigated.
In addition, the dopamine transporter (DAT)
has been posited to be involved in Mn uptake in
the brain. Being highly expressed in in the axons,
dendrites and cell bodies of neurons in the SNpc,
globus pallidus and striatum it normally functions to
induce reuptake of dopamine into presynaptic vesicles
(122). Studies point out that DAT and Mn overload
impact each other. The usage of DAT inhibitors as well
as DAT knockout animals resulted in a reduced Mn
accumulation in certain brain areas as the striatum,
while affecting Mn accumulation in brain regions not
expressing DAT (123, 124). Selectivity to the DAT was
veried, since inhibition of the serotonin transporter
or norepinephrine transporter did not show this effect
(125). Acute Mn administration in animals as well as
patients chronically exposed to Mn show decreased
DAT levels (123, 126). It has also been observed that
the presence of Mn induces the internalization of DAT
in transfected HEK cells (127).
Chronic Mn exposure is associated with
decreased levels of choline in the hypothalamus and
thalamus (128). However, whether choline transporters
play a direct role in Mn import, need to be investigated
in further studies (129).
At the neuronal level, α-synuclein (α-Syn) is
believed to contribute to Mn homeostasis in neurons
(130). Overexpression of increased intracellular Mn
levels, whereas levels of Ca, Zn, K, P, and S were
signicantly decreased with not altering the expression
patterns of DMT1, voltage-gated Ca-channels and
ferroportin. Thus, α-Syn may act as an intracellular Mn
store and neurotoxicity associated with PD might be
mediated via regulation of transition metal levels and
the metal-binding capacity of α-Syn (130).
In addition, the Cu-dependent ferroxidase
ceruloplasmin (Cp) is actually discussed to contribute
to Mn uptake. While previously it was proposed that
Role of manganese in humans
1662 © 1996-2018
Cp oxidized Mn to its trivalent state and loaded onto
Tf (93, 131), a more recent study did not nd any
difference between control and a ceruloplasminemic
mouse in trivalent Mn bound to Tf. The data pointed
out further that Cp affects the tissue distribution of Mn
and increases oxidative stress in the brain (132).
4.2.2. Mn efux: Ferroportin, SLC30A10, NCX
In addition to import, Mn efux plays a central
role in regulating intracellular concentrations of this
metal in the CNS. Compared with Mn import, less is
known about Mn transporters/channel proteins that
participate in Mn efux. Currently, plasma membrane
localized exporters include ferroportin (Fpn),
SLC30A10 and sodium-calcium exchanger (NCX).
Fpn is the only known mammalian Fe
exporter, and is expressed in brain cells including
neurons, astrocytes, the endothelial cells of the
BBB, oligodendrocytes, the choroid plexus and
ependymal cells (133). However, whether or not
Fpn exports Mn and plays a role in Mn homeostasis
remain controversial. While some studies report the
induction of Fpn protein by Mn exposure (134, 135),
other reports indicate treatment with Mn has no effect
on gene expression (136). Xenopus laevis oocytes
expressing human Fpn showed lower intracellular
Mn and higher extracellular Mn (135). In an animal
model by using atiron (ffe/+) mice, a genetic model of
Fpn deciency, evidence suggest that Fpn deciency
impairs Mn metabolism. The authors suggest further
that atiron mice provide an excellent genetic model
to explore the role of this exporter in Mn homeostasis
(137). In addition, in C. elegans, a genetic contribution
on the Mn export has been shown. pdr-1 (PD
related-1) imparts a risk for autosomal recessive,
early-onset PD, and encodes for the E3 ubiquitin
ligase parkin. Within the ubiquitin proteasome
system that targets substrates for degradation, parkin
functions in multiple processes, among them is the
stabilization of cytoskeletal components associated
with actin laments in neuronal and non-neuronal
cells. Recently, studies in C. elegans have shown
that a genetic predisposition of PD by means of a
loss of pdr-1, can modulate Mn export through altered
transporter expression of Fpn. Overexpression of
fpn-1.1. in worms lacking pdr-1, showed evidence
for attenuation of several endpoints of Mn-induced
toxicity (138).
SLC30A10 (or ZnT-10) is one of the 10
solute carrier family 30 (SLC30) transporters (ZnTs,
Zn transporters). Interestingly, although SLC30A10
mediated Mn efux, SLC30A1-8 transport Zn.
Molecular characterizations as well as crystal
structures revealed fundamental differences between
a crucial Zn binding site in the transmembrane
domain and the corresponding putative metal binding
site of SLC30A10 (139) (140, 141). Residues in the
transmembrane and C-terminal domains together
confer optimal manganese transport capability to
SLC30A10 (141). SLC30A10 is localized to the plasma
membrane and is functional in manganese metabolism
by efuxing cytosolic Mn (142, 143). Recent ndings
identied the SLC30A10 gene as the disease-causing
gene in an inherited Mn overload syndrome. Mutations
of the SLC30A10 gene result in parkinsonism
with hypermanganesemia along with dystonia,
polycythemia, characteristic MRI brain ndings in
the basal ganglia, and chronic liver disease (8, 144).
Currently, it is the only known protein associated with
the rst hereditary or familial form of Mn-induced
parkinsonism underlining its critical role in regulating
CNS Mn homeostasis. The new form of familial
parkinsonism has been reported rst in 2008 by Tuschl
et al in a 12-year old girl with hypermanganesaemia,
liver cirrhosis, an extrapyramidal motor disorder and
polycythaemia (145). The brother had the same
symptoms but did not survive. While not being
exposed through elevated Mn from environmental
or occupational sources, the patient had ~ 10-fold
increase in blood Mn levels and the MRI studies point
out Mn deposition in the basal ganglia (145). Almost
10 years later, about 13 families have been reported
on, for a total of at least 25 affected individuals with
the same clinical picture as just described (146, 147).
All affected patients carried homozygous mutations
in the gene coding for SLC30A10 and thirteen
causative mutations have been reported so far (147).
The patients have never been exposed to high Mn-
containing environment while all patients exhibited
10–20 fold increase in blood Mn levels concomitant
with Mn deposition in the basal ganglia. This indicates
that homeostatic control of Mn was compromised in the
cases (8, 146, 147). Recent ndings provided insights
in the molecular mechanisms. In vitro as well as in
vivo studies discovered that SLC30A10 functioned as
a cell-surface-localized manganese efux transporter
that protected against Mn toxicity. A mutation of
SLC30A10 resulted in a heightened sensitivity to Mn
toxicity (139, 143). Experiments using a full-body,
constitutive Slc30a10 knockout mice unexpectedly
exhibited extensive alterations in their thyroid while
brain and liver were largely unaffected (139). Thus
far, the relationship between thyroid function and
Mn toxicity has received little attention, and whether
human patients of Mn toxicity develop hypothyroidism
is unknown and needs to be determined in future
studies.
Recent cardiac studies suggested the role of
sodium-calcium exchanger (NCX) in Mn accumulation
and retention. Studies examined the temporal features
of cardiac Mn2+
efux by implementing MRI and inhibiting
the NCX with SEA0400. This inhibition was shown to
result in an increase of Mn2+ blocks manganese efux
in mouse and rat tissues (148-150). More recently, the
Role of manganese in humans
1663 © 1996-2018
inhibition of the NCX channel (inhibitor KB-R7943) was
shown to increase cellular Mn levels in immortalized
mouse striatal neuroprogenitors (151). However,
additional studies are needed in order to determine the
role of NCX under normal Mn neuronal homeostatic
conditions.
4.3. Intracellular Mn transporters
Despite being expressed in the plasma
membrane, transporters can be further expressed
in the organelles and thus ensure subcellular Mn
transport. Regarding their intracellular distribution,
only a limited number of studies is available. Data
suggested that the lysosomes, the Golgi apparatus,
the endosome, mitochondria as well as the nucleus
may be signicant pools for intracellular Mn (152-156).
4.3.1. Endosome: TfR and DMT1
In addition to the membrane transporters,
Mn can be transported into the cytosol via the ligand-
receptor endocytosis mechanism, which is mediated
by TfR and DMT1. In mouse hippocampal and
striatal neuronal cells, Mn3+/Tf/TfR complex has been
found in a region close to the mitochondrial network,
presumably endosomes, via the endocytic transport
(53). Later, Mn3+ dissociates from Tf/TfR complex
after endocytosis. As a unstable and reactive oxidant,
Mn3+ has to be reduced to Mn2+, a process which is
mediated by ferrireductase to avoid oxidative stress (9,
53, 157). Analogous to TfR, DMT1 is also expressed
in the endosome and transports Mn2+ from endosome
lumen to cytoplasm (9, 157).
4.3.2. Lysosome: PARK9/ATP13A2
The ATP13A2 gene (PARK9) encodes
a lysosomal type 5 P-type ATPase. Its substrate
specicity and physiological function are unknown,
however studies suggest it is involved in lysosomal
degradation of proteins, Mn homeostasis, and most
recently Zn transport (158, 159). Mutations in ATP13A2
have been associated with an autosomal recessive
levodopa-responsive early-onset parkinsonism,
known as Kufor–Rakeb syndrome (160, 161). In in
vitro studies ATP13A2 protected cells as neuronal
cultures from Mn-induced cell death in response to
Mn treatment (160, 162, 163). In primary rat neurons,
ATP13A2 levels were increased in the presence of
excess Mn, while expression of wild-type ATP13A2
lowered intracellular Mn levels and prevented Mn-
induced neuronal death (163). These data show the
involvement of ATP13A2 in Mn homeostasis which is
further underlined by polymorphisms of ATP13A2 to
modify the effects of Mn on motor function in an elderly
population (164). To modify the activity of ATP13A2
is another approach for a therapeutic strategy. The
catalytically active ATP13A2 offers cellular protection
against rotenone-induced mitochondrial stress, which
relies on the availability of the lipids phosphatidic
acid (PA) and phosphatidylinositol(3,5)bisphosphate
(PI(3,5)P2). Thus, the N-terminal binding of PA and
PI(3,5)P2 emerges as a key to unlock the activity of
ATP13A2, which may offer a therapeutic strategy to
activate ATP13A2 (165). Besides regulating Mn toxicity,
ATP13A2 is also known to regulate α-Syn toxicity.
ATP13A2 expression can suppress α-Syn toxicity
in yeast and rescue α-Syn-induced dopaminergic
degeneration in primary neuronal culture (160).
However, a recent study did not nd neuroprotection
when ATP13A2 and α-Syn were co-expressed using
viral vector technology in the SN in rats (161). Another
study supports a relationship between ATP13A2, Mn,
and α-Syn accumulation in vivo. Older ATP13A2-
decient mice showed Mn enhanced sensorimotor
function, increased autouorescence in the SN, and
increased insoluble α-Syn in the ventral midbrain.
The authors also found increased Mn concentration
in the brain with higher levels in Mn-treated ATP13A2
mutants as compared to the control animals (158).
However, another study in a different ATP13A2
knockout mouse showed age-dependent motor
impairments, gliosis, accumulated ubiquitin protein
aggregates, and endolysosomal abnormalities but no
aberrant α-Syn up to 18 months of age (166). Besides
the existing in vitro and in vivo studies, no direct Mn
efux activity for ATP13A2 has been demonstrated up
to now. Therefore, additional studies are necessary
especially also whether patients who harbor mutations
in this gene also exhibit Mn deposition in specic brain
regions.
4.3.3. Golgi: SPCA1, HIP14, SLC30A10, calcium
channels
Synchrotron X-ray uorescence nanoimaging
has established the Golgi apparatus is the cellular
site of preferential accumulation of Mn (153, 167).
A Mn transporter localized in the Golgi apparatus is
the secretory pathway Ca2+/ Mn2+ ATPase isoform 1
(SPCA1) encoded by ATP2C1. It is a known Ca2+/ Mn2+
transporter pump and is the only known P-type ATPase
having a high afnity to transport Mn2+ (168, 169).
Silencing of SPCA1 as well as deciency resulted in
an extreme sensitivity to high Mn concentrations (140,
169). SPCA1 carrying specic mutations that could
potentially increase its Mn2+ pumping activity as the
point mutation Q747A has been shown therapeutically
useful in the management of manganism (170). Mn has
further been shown to induce degradation of GPP130,
a membrane protein that cycles between the Golgi and
endosomes (171). Therefore, it is suggested that G
PP130 may be involved in Mn homeostatic regulation.
GPP130 is viewed as a Mn sensor, potentially useful
for monitoring Mn levels. SPCA1 is required for Mn to
reach the Golgi lumen where it binds to GPP130 and
induced GPP130 oligomerization in the Golgi. This
Role of manganese in humans
1664 © 1996-2018
results in sorting to the oligomer and secretion of Mn
from the cell (172).
Additional Mn transporters expressed in
the Golgi apparatus are HIP14, SLC30A10 as well
as calcium channels which have already been
described in this review. Additionally, variants
in ZIP8 impair the function of a Golgi enzyme
essential for biosynthesis of the carbohydrate part
of glycoproteins (110, 170). At higher concentrations
Mn may not be stored properly in the Golgi apparatus
and other organelles may be impacted by Mn.
An drug-induced collapse of the Golgi apparatus,
results in the striking intracellular redistribution of
Mn with Mn accumulation in the cytoplasm and the
nucleus (153). This lead to the assumption that the
Golgi apparatus might be a storage site and critical
target for Mn toxicity and altered functions might be
involved in Manganism.
4.3.4. Mitochondria: DMT1, TfR and Ca uniporter
Excess Mn has been reported to disrupt
energy production and induce oxidative stress in the
mitochondria (173-175). In addition, the highest Mn
accumulation rate was observed in the mitochondria
of astrocytes and neurons, compared with other
organelles after chronic Mn exposure (176). However,
the regulation of Mn homeostasis in this organelle
remains largely unknown. Mn transporters expressed
in the mitochondria include DMT1 in the outer
mitochondrial membrane (104), the TfR, Ca transporter
as well as citrate transporter (177, 178). Cytosolic Mn2+
is imported in the mitochondrial lumen by Ca uniporter,
while excessive Mn is supposed to be exported through
Na-independent mechanisms (179-181). Gavin et al.
(1999) further indicated that a slow efux of Mn by
mitochondria accounts for the excess accumulation of
Mn ions in this subcellular organelle (177). Other studies
did not observe Mn accumulation in the mitochondria
(152, 154).
4.3.5. Nucleus: unknown
From experimental evidences the nucleus
is supposed to be the largest intracellular Mn pool.
For example, in rat striatum and globus pallidus, the
highest Mn level was observed in the heterochromatin
and nucleolus, after moderate Mn exposure (176).
But to our knowledge there is no mechanistic study
to investigate the reason for its high capacity to
accumulate Mn. Discussed are hypothesis that Pirin,
a highly conserved nuclear protein that is exclusively
localized within the nucleoplasm and predominantly
concentrated within dot-like sub-nuclear structures,
may play a role in Mn transport (154). The highly
conserved metal binding site in the N-terminal β-barrel
of Pirin may allow Mn to replace Fe and therefore offer
a depot for Mn ions (182).
5. SUMMARY AND FUTURE DIRECTIONS
In the last decade, research on Mn-related
toxicity has advanced the understanding on mechanisms
associated with Mn intoxication, providing scientic
evidence for Mn regulation and potential therapeutics to
treat people with Mn poisoning.
Given that Mn is a required nutrition but also
an abundant metal on the earth, every day people have
contact with Mn through environmental, occupational
and medical exposure routes (Fig. 1). Currently,
dietary consumption is the primary Mn exposure
route, about 3-5% of ingested Mn is absorbed in blood
stream via the GI tract through passive diffusion or
active transport, regulated by Mn transporters and
Mn binding proteins. Mn absorption via ingestion
accounts for the highest Mn amount and is also the
safest way. Abnormal Mn uptake though upon in utero
exposure, inhalation, intravenous administration and
dermal exposure (Fig. 1) can bypass the absorptive
regulation afforded by GI tract, exceed the capability
of liver elimination or directly deposit in the brain, with
ensuing Mn intoxication. Once in the blood stream,
Mn is rapidly distributed to different tissues. The liver,
bone, pancreas, kidney and brain are the ve major
organs (from high to low) containing highest Mn
level in human body (Fig. 1). Importantly, the brain
is the primary target of Mn poisoning although it is
not the tissue with the highest Mn concentration. Mn
gets delivered in the brain through the blood-brain
barrier (BBB), the blood-cerebrospinal uid (CSF)
barrier and the olfactory tract, which is regulated by
various Mn transporters. The daily absorption amount
usually exceeds the actual need, thus extra Mn has
to be eliminated. Fecal hepatobiliary excretion is the
primary elimination route, through which excess Mn is
conjugated in the bile and excreted in feces. Besides,
Mn can be excreted though urine, milk and sweat as
well, although the amount is very limited.
As a requisite nutrition at low levels but also
a toxicant at high concentrations, Mn in the human
body has to be tightly regulated. At the cellular level,
this homeostasis is achieved by various types of Mn
transporters and regulators. On cell surface, DMT1,
TfR, ZIP8/ZIP14, DAT, calcium channels, citrate
transporter, choline transporter and ceruloplasmin
regulate Mn inux from the cell matrix, while
SLC30A10, Fpn and NCX mediate cytosolic Mn efux.
Intracellularly, the Mn/Tf/TfR complex can be packed
in endosomes for endocytosis and nally released
into cytosol by endosomal DMT1. On the other
hand, PARK9/ATP13A2 transports cytosolic Mn into
lysosomes, meanwhile, SPCA1, HIP14, SLC30A10
and calcium channels are able to pack Mn in the Golgi
apparatus. Once Mn is sorted out in lysosomes and
the Golgi, it is secreted from cells. In addition, the
mitochondrion and nucleus are the two organelles
Role of manganese in humans
1665 © 1996-2018
with the highest Mn concentrations, and they play a
role as Mn pools for its storage. The uptake, efux and
subcellular transport of Mn are facilitated by various
transporters to obtain a homeostasis (Fig. 1). However,
environmental or genetic risk factors may disrupt this
balance and result in Mn intoxication (Fig. 1).
Given the exposure routes, absorption,
distribution and elimination of Mn described above,
several groups of people are at high risk of Mn poisoning.
The rst group are neonates. Infants tend to absorb
various metals including Mn for their development;
however, the elimination system is still developing,
thus less capable to extrude excessive Mn. The most
important infant foods-formula and milk, both contain
signicant amounts of Mn, which might be a potential
risk and require a new industrial standard. Importantly,
premature infants receiving total parental nutrition
(TPN) are at highest risk, as they absorb 100% of Mn
from TPN. Second, children exposed to high levels of
Mn through drinking water or living close to high Mn
environment have a higher risk of Mn poisoning as
developing children tend to absorb higher levels of Mn.
Third, industrial workers performing welding, smelting,
mining, manufacture of steel, batteries, glass, ceramics,
cosmetics, leather, reworks and other textiles should
be aware of potential risk. Fourth, patients with liver
problems, such as hepatic encephalopathy or liver
failure, are less capable to eliminate extra Mn. They
tend to accumulate Mn in the body even without high
environmental exposure. Fifth, people carrying certain
genetic mutations, such as SLC30A10, ZIP14, PARK9
and SPCA1, are also at risk of Mn intoxication. Sixth,
people under iron deciency condition tends to have
Mn accumulation in their body as iron deciency
will increase the activity of Fe/Mn transporters and
upregulate the absorption rate of Mn. Last but not
least, methcathinone abusers has become another
susceptible group with the spreading of this drug.
Although the toxic effect of Mn in neonates and
children has been well-studied in TPN, administration
by government to limit Mn contents in infant foods and
nutrition supplements remains a contemporary health
Figure 1. Manganese metabolism and regulation in humans. Human exposure to Mn arises from both natural and anthropogenic sources, including
environmental, occupational and medical exposure. Mn enters human body via ingestion, utero exposure, inhalation, intravenous administration and
dermal exposure. Once absorbed, Mn enters the blood stream and gets distributed via blood circulation. This process is regulated in various organs
including blood, liver, pancreas, kidney, bone as well as the brain. On the cellular level, Mn homeostasis is maintained by both membrane transporters and
subcellular transporters. The membrane transporters include importers and exporters. Mn is further subcellular distributed and regulated in endosome,
lysosome, Golgi, mitochondria and nucleus. A loss of Mn homeostasis is documented to lead to devastating neurological impairment. This disease,
termed as “manganism” shares a similar neuropathology as Parkinson’s disease (PD).
Role of manganese in humans
1666 © 1996-2018
issue. Establishing standards is of great urgency
especially in TPN and potentially in infant formula and
milk as well.
While great strides have been made in the
past years, the complete picture of Mn metabolism and
homeostasis remains to be mapped out. Advanced
biomarkers or measuring techniques are needed to
monitor body Mn levels, especially for chronic Mn
accumulation. As blood Mn is very dynamic and only
represents current body Mn levels in a relatively short
term, patients with low blood Mn after chelation therapy
might still suffer from Mn-induced neurotoxicity due to
slow release of Mn from other tissues accumulated in
the past. Bone Mn is a good biomarker for this purpose,
given that bone stores the largest amount of Mn in
human body and bone Mn has a long half-life (skeleton
bone 8.5. years). Recent techniques such as in vivo
neutron activation analysis (IVNAA) allow non-invasive
measurement of bone Mn levels, thus are of great help
to access chronic Mn accumulation and monitor Mn
levels across developmental stages in children. Brain
is the primary target of Mn poisoning. As for regulation
of Mn homeostasis, although we have identied a few
transporters capable to transport Mn, a large numbers
of regulator proteins remain to be identify. Besides,
among these known transporters, actually none of
them has been proved as a Mn specic transporter.
Most of them facilitate couple metal ions inux or efux
with highest afnity to other metals rather than Mn.
SLC30A10 could be a potential candidate, but more
research is needed to conrm that. In addition, within a
cell, the nucleus is the largest Mn storage site with the
highest Mn concentration. However, regulation of Mn
homeostasis in this organelle remain blank due to very
few intracellular transporters identied there. A forward
or reverse genetic screen to nd these transporters or
regulators is of great interest and priority to understand
Mn homeostasis in cells and in human body.
6. ACKNOWLEDGEMENTS
Drs. P. Chen and J. Bornhorst contributed
equally to this work. The manuscript was supported
by NIH grant NIEHS R01 10563 and the “Deutsche
Forschungsgemeinschaft” (DFG) (BO 4103/2-1). This
work was further funded by TraceAge - DFG Research
Unit on Interactions of essential trace elements in
healthy and diseased elderly, Potsdam-Berlin-Jena
(FOR 2558/1). The authors declare that they have no
conict of interest.
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Role of manganese in humans
1679 © 1996-2018
DOI: 10.1073/pnas.1221743110
PMid:23716661 PMCid:PMC3683729
Key Words: Manganese, Metal Metabolism,
Homeostasis, Blood-Brain Barrier, Neurotoxicity,
Transporters, Review
Send correspondence to: Pan Chen,
Department of Molecular Pharmacology, Albert
Einstein College of Medicine, Forchheimer 209,
1300 Morris Park Avenue, Bronx, NY 10461, Tel:
718-430-4047, Fax: 718-430-8922, E-mail: pan.
chen@einstein.yu.edu
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Mutations in human ZIP14 have been linked to symptoms of the early onset of Parkinsonism and Dystonia. This phenotype is likely related to excess manganese accumulation in the CNS. The metal transporter ZIP14 (SLC39A14) is viewed primarily as a zinc transporter that is inducible via proinflammatory stimuli. In vitro evidence shows that ZIP14 can also transport manganese. To examine a role for ZIP14 in manganese homeostasis, we used Zip14 knock-out (KO) male and female mice to conduct comparative metabolic, imaging, and functional studies. Manganese accumulation was fourfold to fivefold higher in brains of Zip14 KO mice compared with young adult wild-type mice. There was less accumulation of subcutaneously administered 54Mn in the liver, gallbladder, and gastrointestinal tract of the KO mice, suggesting that manganese elimination is impaired with Zip14 ablation. Impaired elimination creates the opportunity for atypical manganese accumulation in tissues, including the brain. The intensity of MR images from brains of the Zip14 KO mice is indicative of major manganese accumulation. In agreement with excessive manganese accumulation was the impaired motor function observed in the Zip14 KO mice. These results also demonstrate that ZIP14 is not essential for manganese uptake by the brain. Nevertheless, the upregulation of signatures of brain injury observed in the Zip14KOmice demonstrates that normal ZIP14 function is an essential factor required to prevent manganese-linked neurodegeneration.
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