GO:0006828 manganese ion transport: Transport Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0006828 manganese ion transport describes the directed movement of manganese (Mn) ions into, out of, or within a cell, or between cells, via transporters or pores.
• Manganese is an essential trace metal cofactor for enzymes including mitochondrial superoxide dismutase (SOD2), arginase, and glutamine synthetase, so its transport must be tightly controlled.
• Key transporters include SLC11A2 (DMT1), SLC30A10, SLC39A8 (ZIP8), SLC39A14 (ZIP14), and the transferrin receptor pathway, which together mediate uptake, intracellular distribution, and efflux.
• Manganese transport is intimately linked to iron metabolism; iron deficiency can increase manganese uptake and toxicity, while iron overload can alter manganese distribution.
• Dysregulated manganese transport causes hypermanganesemia with dystonia, polycythemia, and cirrhosis (SLC30A10 deficiency) and contributes to neurotoxicity resembling Parkinsonism.
• Manganese-enhanced MRI (MEMRI) exploits manganese as a calcium analog to trace neuronal connectivity and myocardial function, directly relying on manganese transport mechanisms.
Description
Manganese ion transport (GO:0006828) is the biological process by which manganese (Mn) ions are moved across cellular membranes or within cells by dedicated transporters or pores. Manganese is an essential micronutrient that serves as a cofactor for enzymes involved in antioxidant defense, amino acid metabolism, and glycosylation, but excess manganese is neurotoxic. Therefore, organisms have evolved sophisticated transport systems to maintain manganese homeostasis at the cellular and systemic levels. Understanding this process is critical for researchers in neuroscience, nutrition, toxicology, and membrane transport biology. The transport of manganese is mediated by a suite of membrane proteins, including members of the SLC11, SLC30, and SLC39 families, as well as transferrin-mediated uptake pathways. Recent structural and mechanistic studies have begun to reveal how these transporters recognize and translocate manganese with high specificity. This article provides a comprehensive overview of manganese ion transport, its molecular players, regulation, disease relevance, and the experimental methods used to study it.
manganese ion transport At A Glance
| GO ID | GO:0006828 |
|---|---|
| GO term | manganese ion transport |
| Ontology | biological_process |
| Synonym | None listed in QuickGO |
| Major function | Directed movement of manganese ions across membranes or within cells |
| Cellular locations | Plasma membrane, endosomes, Golgi, mitochondria, and other organellar membranes |
| Key transporters | SLC11A2 (DMT1), SLC30A10, SLC39A8 (ZIP8), SLC39A14 (ZIP14), transferrin receptor |
| Associated diseases | Hypermanganesemia with dystonia, polycythemia, cirrhosis; manganism; iron-related disorders |
| Research methods | Manganese-enhanced MRI, radiotracer flux assays, electrophysiology, CRISPR screens, structural biology |
What Is GO:0006828?
According to the Gene Ontology, manganese ion transport (GO:0006828) is defined as the directed movement of manganese (Mn) ions into, out of, or within a cell, or between cells, by means of some agent such as a transporter or pore. This process encompasses all mechanisms that mediate the translocation of Mn2+ or other manganese ion species across biological membranes, including active transport, facilitated diffusion, and channel-mediated movement. It is a biological_process term that can occur at the plasma membrane, organellar membranes, or within cellular compartments.
Why Is manganese ion transport Important in Cell Biology?
Manganese ion transport is essential for human health because manganese is required for the activity of key enzymes such as mitochondrial superoxide dismutase (SOD2), arginase, and glutamine synthetase, yet excessive intracellular manganese is toxic, particularly to dopaminergic neurons. The balance between manganese uptake, distribution, and efflux is maintained by specific transporters, and their dysfunction leads to severe diseases including hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC) and manganese-induced neurotoxicity resembling Parkinsonism. Moreover, manganese transport intersects with iron metabolism, and disturbances in iron status can exacerbate manganese toxicity. Studying manganese ion transport is therefore critical for understanding metal homeostasis, developing therapies for related disorders, and advancing imaging techniques such as MEMRI.
• Manganese is an essential cofactor for antioxidant enzymes, so its transport is required for cellular defense against oxidative stress.
• Dysregulated manganese transport causes hypermanganesemia with dystonia, polycythemia, and cirrhosis due to mutations in SLC30A10.
• Manganese overload is linked to manganism, a Parkinson-like neurodegenerative condition affecting basal ganglia.
• Manganese transport influences iron homeostasis, and iron deficiency can enhance manganese uptake and toxicity.
• Manganese-enhanced MRI (MEMRI) relies on manganese transport to map neuronal connections and myocardial function.
• Transporters such as DMT1 and SLC30A10 are emerging drug targets for metal-related disorders.
• Manganese transport is important in environmental contexts, such as the fate of pharmaceuticals in manganese oxide coated sand columns.
• Understanding manganese transport aids in designing separation membranes and environmental remediation strategies.
• Manganese transport mechanisms are conserved from bacteria to humans, offering model systems for study.
• CRISPR screens can identify novel genes regulating manganese transport and toxicity.
What Happens During manganese ion transport?
Uptake of manganese across the plasma membrane
In simple terms: Manganese enters the cell through specialized transporter proteins.
Manganese uptake into cells is primarily mediated by the divalent metal transporter 1 (DMT1, SLC11A2), which also transports iron and other divalent metals. DMT1 is a proton-coupled transporter that moves Mn2+ across the plasma membrane and endosomal membranes. Other uptake routes include ZIP8 (SLC39A8) and ZIP14 (SLC39A14), which are zinc transporters that also accept manganese. Transferrin-bound manganese can be taken up via transferrin receptor-mediated endocytosis. The relative contribution of each pathway depends on cell type and physiological conditions.
Intracellular distribution and organellar transport
In simple terms: Once inside, manganese is moved to different compartments where it is needed.
After uptake, manganese is distributed to organelles including mitochondria, Golgi apparatus, and the nucleus. Mitochondria require manganese for SOD2, and specific transporters such as SLC30A10 and members of the SLC39 family may mediate mitochondrial manganese import. The Golgi apparatus is a major manganese store and is involved in glycosylation reactions. SLC30A10 localizes to the Golgi and can also traffic to the plasma membrane to mediate efflux. Intracellular manganese homeostasis is maintained by coordinated action of uptake, storage, and efflux transporters.
Efflux and excretion of manganese
In simple terms: Excess manganese is pumped out of cells to prevent toxicity.
Cellular manganese efflux is primarily mediated by SLC30A10, a zinc transporter that also transports manganese. SLC30A10 is localized to the plasma membrane and the Golgi apparatus, where it can remove manganese from the cytosol. Mutations in SLC30A10 cause manganese accumulation and severe disease. In the liver, manganese is excreted into bile, a process that requires SLC30A10 function. Other transporters such as ferroportin may also contribute to manganese efflux under certain conditions.
Systemic manganese transport and blood-brain barrier
In simple terms: Manganese travels through the body and enters the brain via specific transport systems.
Systemic manganese transport involves absorption in the intestine, distribution via the bloodstream, and excretion through the liver. Manganese in blood is bound to transferrin and albumin, and it can cross the blood-brain barrier via transferrin receptor-mediated endocytosis and other transporters such as ZIP8 and ZIP14. Within the brain, manganese is transported along axons, which is the basis for MEMRI. The blood-brain barrier and blood-cerebrospinal fluid barrier regulate manganese entry into the central nervous system, and their dysfunction can lead to manganese neurotoxicity.
Regulation of manganese transport by iron status
In simple terms: Iron levels affect how much manganese gets into cells.
Iron and manganese share transport pathways, particularly DMT1 and ferroportin. Iron deficiency increases DMT1 expression, which can enhance manganese uptake and lead to manganese accumulation in the brain. Conversely, iron overload may compete with manganese for transport, altering manganese distribution. This interplay is important in conditions such as hereditary hemochromatosis and iron-deficiency anemia, where manganese homeostasis can be disrupted. Dietary factors and metal exposure also influence manganese transport.
Key Genes Involved in GO:0006828 manganese ion transport
The following genes encode proteins that directly mediate or regulate manganese ion transport, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SLC11A2 (DMT1) | Proton-coupled transporter for Mn2+ and Fe2+ uptake | Key mediator of manganese absorption; target for iron-manganese interaction studies |
| SLC30A10 | Manganese efflux transporter at plasma membrane and Golgi | Mutations cause hypermanganesemia; structural studies reveal transport mechanism |
| SLC39A8 (ZIP8) | Zinc/manganese uptake transporter | Polymorphisms linked to manganese homeostasis and disease risk |
| SLC39A14 (ZIP14) | Zinc/manganese uptake transporter | Mediates manganese uptake in liver and brain; linked to neurotoxicity |
| SLC40A1 (Ferroportin) | Iron exporter that also transports manganese | Contributes to manganese efflux; interplay with iron metabolism |
| TFRC (Transferrin receptor) | Mediates transferrin-bound manganese uptake | Important for brain manganese delivery and MEMRI |
| SOD2 | Manganese-dependent superoxide dismutase | Requires manganese as cofactor; readout of manganese status |
| ARG1 | Arginase requiring manganese | Manganese-dependent enzyme in urea cycle |
| GLS (Glutaminase) | Manganese-dependent enzyme | Manganese cofactor for glutamine metabolism |
| ATP7A | Copper transporter with manganese transport capacity | May influence manganese distribution |
| ATP7B | Copper transporter with manganese transport capacity | Potential role in manganese homeostasis |
| SLC30A1 (ZnT1) | Zinc transporter possibly transporting manganese | Candidate manganese transporter |
| SLC30A2 (ZnT2) | Zinc transporter possibly transporting manganese | Expressed in mammary gland; may affect manganese secretion |
| SLC39A10 (ZIP10) | Zinc transporter with manganese transport activity | Potential manganese uptake mediator |
| SLC39A6 (ZIP6) | Zinc transporter with manganese transport activity | May contribute to manganese uptake |
| MTF1 | Metal-responsive transcription factor | Regulates expression of metal transporters including manganese-related genes |
| NCOA4 | Ferritinophagy receptor | May influence manganese release from stores |
| HAMP (Hepcidin) | Regulates iron and manganese transport | Links systemic iron status to manganese distribution |
How Is manganese ion transport Regulated?
Manganese ion transport is regulated at multiple levels. Transcriptionally, metal-responsive transcription factor 1 (MTF1) controls the expression of several zinc and manganese transporters in response to metal availability. Iron status strongly influences manganese transport: iron deficiency upregulates DMT1, increasing manganese uptake, while iron overload can downregulate DMT1 and alter manganese distribution. SLC30A10 expression is regulated by manganese levels and possibly by other metals, and its localization between Golgi and plasma membrane is dynamic. Post-translational modifications and protein-protein interactions may also modulate transporter activity. Additionally, systemic factors such as hepcidin regulate iron and manganese export from cells.
manganese ion transport and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SLC30A10 | Hypermanganesemia with dystonia, polycythemia, cirrhosis | Knockout and point-mutation knock-in cell models; patient-derived iPSCs |
| SLC11A2 (DMT1) | Iron deficiency anemia and manganese neurotoxicity | Knockout and overexpression cell lines; intestinal organoids |
| SLC39A14 (ZIP14) | Manganese-induced neurotoxicity | Knockout mice and cell models; blood-brain barrier models |
| SLC39A8 (ZIP8) | Manganese homeostasis and congenital disorders of glycosylation | Knockout and point-mutation knock-in cells; zebrafish models |
| SLC40A1 (Ferroportin) | Iron overload and manganese imbalance | Knockout and overexpression cell lines; liver organoids |
Hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC)
Mutations in SLC30A10 cause HMDPC, an autosomal recessive disorder characterized by manganese accumulation in the liver and brain, leading to dystonia, polycythemia, and cirrhosis. SLC30A10 is a manganese efflux transporter, and its loss of function results in impaired manganese excretion and subsequent toxicity. This disease highlights the critical role of manganese transport in human health and provides a model for studying manganese homeostasis.
Manganese neurotoxicity and Parkinsonism
Excessive manganese accumulation in the brain, particularly in the basal ganglia, causes a Parkinson-like syndrome known as manganism. Dysregulated transport across the blood-brain barrier, often involving DMT1, ZIP8, and ZIP14, contributes to manganese neurotoxicity. Chronic exposure to high manganese levels, as seen in occupational settings, can lead to irreversible neurological damage. Understanding manganese transport mechanisms is essential for developing therapies for manganism.
Iron metabolism disorders and manganese imbalance
Disorders of iron metabolism, such as hereditary hemochromatosis and iron-deficiency anemia, can disrupt manganese transport due to shared transporters like DMT1 and ferroportin. Iron deficiency increases manganese absorption and can lead to manganese accumulation in the brain, exacerbating neurotoxicity. Conversely, iron overload may alter manganese distribution and excretion. These interactions underscore the need to consider both metals in clinical management.
Manganese transport in cancer and other diseases
Altered manganese transport has been implicated in cancer biology, as manganese is required for antioxidant enzymes and metabolic reprogramming. SLC30A10 and other transporters may influence tumor growth and metastasis, though the evidence is still emerging. Additionally, manganese transport is relevant to liver diseases, neurodegenerative disorders, and metabolic syndromes. Further research using CRISPR models is needed to clarify these roles.
From manganese ion transport-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does SLC30A10 mediate manganese efflux? | SLC30A10 knockout and overexpression cell lines; manganese flux assays |
| What is the structural basis of manganese transport by DMT1? | Point mutations in SLC11A2 combined with cryo-EM and transport assays |
| How does ZIP14 contribute to brain manganese uptake? | SLC39A14 knockout mice and blood-brain barrier cell models |
| What are the effects of manganese overload on mitochondrial function? | SOD2 knockout and overexpression cells; manganese-treated mitochondria |
| Can CRISPR screens identify novel manganese transporters? | Genome-wide CRISPR knockout library screening in manganese-sensitive cells |
| How does iron status affect manganese transport? | DMT1 knockout and iron-deficient/overloaded cell models; ferroportin mutants |
How to Study the manganese ion transport Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Manganese-enhanced MRI (MEMRI) | Manganese accumulation and transport in tissues | Neuronal connectivity mapping and myocardial imaging |
| Radiotracer flux assay | Manganese uptake and efflux rates | Kinetic characterization of transporters |
| Fluorescent manganese indicators | Intracellular manganese concentration changes | Live-cell imaging of transport activity |
| Electrophysiology | Manganese-induced currents | Functional analysis of electrogenic transporters |
| Cryo-electron microscopy | Three-dimensional structure of transporters | Mechanistic studies of SLC11 and SLC30 proteins |
| CRISPR knockout screening | Genes affecting manganese sensitivity | Discovery of novel transport regulators |
| RNA-seq | Transcriptional changes in response to manganese | Identifying regulated transporters and pathways |
| Proteomics | Protein expression and interactions | Mapping manganese transport complexes |
Manganese-enhanced MRI (MEMRI)
MEMRI is a non-invasive imaging technique that uses manganese as a contrast agent to map neuronal connectivity and myocardial function. Manganese ions enter excitable cells through voltage-gated calcium channels and are transported along axons, allowing visualization of active pathways. MEMRI has been used to study axonal transport in the brain and to assess myocardial viability. This method directly relies on manganese transport mechanisms and can be combined with genetic models to dissect transporter function.
Radiotracer and fluorescent flux assays
Radiolabeled manganese (e.g., 54Mn) or fluorescent manganese indicators such as calcein or Fura-2 can be used to measure manganese transport kinetics in cells and isolated membranes. These assays allow quantification of uptake and efflux rates and can be applied to cells expressing wild-type or mutant transporters. They are essential for validating transport activity identified from genomic or structural studies.
Electrophysiology and structural biology
Electrophysiological techniques, such as two-electrode voltage clamp in Xenopus oocytes, can measure manganese-induced currents for electrogenic transporters. Structural biology methods including cryo-electron microscopy and X-ray crystallography have revealed the architecture of SLC11 and SLC30 transporters, providing insights into metal binding and conformational changes. These approaches are critical for understanding the molecular mechanism of manganese transport.
CRISPR screening and bioinformatics
Genome-wide CRISPR knockout or activation screens can identify genes that regulate manganese transport and toxicity. Cells are exposed to varying manganese concentrations, and sgRNA enrichment or depletion is analyzed by next-generation sequencing. Bioinformatics pipelines then map hits to pathways and predict transporter function. This unbiased approach has the potential to uncover novel manganese transport regulators.
How CRISPR Can Be Used to Study GO:0006828 manganese ion transport
Knockout
CRISPR knockout of manganese transporter genes such as SLC30A10, SLC11A2, or SLC39A14 in cell lines can abolish specific transport activities, leading to altered manganese homeostasis. These models are used to study the contribution of each transporter to uptake, efflux, and toxicity. Knockout cells can be challenged with manganese and analyzed for viability, metal content, and downstream signaling.
Point Mutation
CRISPR point mutation can introduce disease-associated missense mutations into transporter genes to mimic human disorders. For example, mutations in SLC30A10 found in HMDPC patients can be knocked into cell lines to study loss of efflux function. Point mutations in DMT1 can reveal residues critical for metal binding and transport. These models provide insights into structure-function relationships.
Knock-in
CRISPR knock-in can be used to tag endogenous transporters with fluorescent or affinity tags for localization and interaction studies. Knock-in of reporter genes under the control of transporter promoters allows monitoring of expression dynamics. Additionally, knock-in of human transporter genes into mouse models can humanize manganese transport for drug testing.
Overexpression
CRISPR activation or lentiviral overexpression can increase the levels of manganese transporters to study their capacity and regulation. Overexpression of SLC30A10 enhances manganese efflux and protects cells from toxicity. Overexpression of DMT1 increases manganese uptake and can sensitize cells to manganese-induced stress. These models are useful for gain-of-function studies and drug screening.
How EDITGENE Supports manganese ion transport Research
Researchers studying manganese ion transport-related genes often need to determine whether a candidate gene is causally involved in manganese uptake, efflux, or toxicity. EDITGENE provides a comprehensive suite of CRISPR-based services to create precisely engineered cell models, enabling functional validation of transporters and regulators in a relevant biological context.
Contact EDITGENE today to design your custom CRISPR model for manganese ion transport research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ATP2C1 Knockout HEK293 Cell Line | EDJ-KQ2711 | Human | 27032 | Details Get a Quote |
| SLC11A1 Knockout HEK293 Cell Line | EDJ-KQ5781 | Human | 6556 | Details Get a Quote |
| ATP2C2 Knockout HEK293 Cell Line | EDJ-KQ6815 | Human | 9914 | Details Get a Quote |
| SLC41A2 Knockout HEK293 Cell Line | EDJ-KQ9981 | Human | 84102 | Details Get a Quote |
| TMEM165 Knockout HEK293 Cell Line | EDJ-KQ11977 | Human | 55858 | Details Get a Quote |
| SLC11A2 Knockout HEK293 Cell Line | EDJ-KQ15293 | Human | 4891 | Details Get a Quote |
| TMEM165 Knockout HeLa Cell Line | EDJ-KQ18205 | Human | 55858 | Details Get a Quote |
| ATP2C1 Knockout A-549 Cell Line | EDJ-KQ24943 | Human | 27032 | Details Get a Quote |
| ATP2C1 Knockout HCT 116 Cell Line | EDJ-KQ24945 | Human | 27032 | Details Get a Quote |
| ATP2C1 Knockout HeLa Cell Line | EDJ-KQ24946 | Human | 27032 | Details Get a Quote |
| SLC41A2 Knockout A-549 Cell Line | EDJ-KQ36925 | Human | 84102 | Details Get a Quote |
| SLC41A2 Knockout HCT 116 Cell Line | EDJ-KQ36926 | Human | 84102 | Details Get a Quote |
| SLC11A2 Knockout HCT 116 Cell Line | EDJ-KQ45991 | Human | 4891 | Details Get a Quote |
| SLC11A2 Knockout HeLa Cell Line | EDJ-KQ45992 | Human | 4891 | Details Get a Quote |
| SLC11A2 Knockout A-549 Cell Line | EDJ-KQ48181 | Human | 4891 | Details Get a Quote |
Frequently Asked Questions About manganese ion transport
What is manganese ion transport?
Manganese ion transport (GO:0006828) is the directed movement of manganese ions into, out of, or within a cell, or between cells, mediated by transporters or pores.
What genes are involved in manganese ion transport?
Key genes include SLC11A2 (DMT1), SLC30A10, SLC39A8 (ZIP8), SLC39A14 (ZIP14), SLC40A1 (ferroportin), and TFRC (transferrin receptor).
How is manganese transported into cells?
Manganese enters cells primarily via DMT1, ZIP8, and ZIP14, and through transferrin receptor-mediated endocytosis of transferrin-bound manganese.
What is the role of SLC30A10 in manganese transport?
SLC30A10 is a manganese efflux transporter localized to the plasma membrane and Golgi; its dysfunction causes manganese accumulation and disease.
What diseases are associated with defective manganese transport?
Mutations in SLC30A10 cause hypermanganesemia with dystonia, polycythemia, and cirrhosis; dysregulated transport also contributes to manganism and iron-related disorders.
How does iron metabolism affect manganese transport?
Iron and manganese share transporters like DMT1; iron deficiency increases manganese uptake, while iron overload can alter manganese distribution.
What is MEMRI and how does it relate to manganese transport?
Manganese-enhanced MRI (MEMRI) uses manganese as a contrast agent that enters cells via calcium channels and transporters, allowing mapping of neuronal connections and myocardial function.
What experimental models are used to study manganese transport?
Common models include CRISPR knockout and knock-in cell lines, overexpression systems, animal models, and imaging techniques like MEMRI.
Can CRISPR screens identify new manganese transporters?
Yes, genome-wide CRISPR screens can uncover genes that regulate manganese sensitivity and transport, as demonstrated in recent studies.
What is the connection between manganese transport and neurotoxicity?
Excessive manganese accumulation in the brain, often due to altered transport, leads to manganism, a Parkinson-like neurodegenerative disorder.
Conclusion
Manganese ion transport (GO:0006828) is a fundamental biological process that maintains cellular and systemic manganese homeostasis. It relies on a network of transporters including DMT1, SLC30A10, ZIP8, and ZIP14, whose coordinated activities prevent manganese deficiency or toxicity. Dysregulation of these transporters causes severe human diseases, notably HMDPC and manganese-induced neurotoxicity. Advances in structural biology, imaging, and CRISPR screening are rapidly expanding our understanding of manganese transport mechanisms. Continued research using precise genetic models will be essential for developing therapeutic strategies targeting manganese transport in disease.
References
- 1. Chen P et al.. 2018. Manganese metabolism in humans.. Front Biosci (Landmark Ed) 23(9):1655-1679 PMID: 29293455
- 2. Shen X et al.. 2025. Molecular mechanisms of SLC30A10-mediated manganese transport.. Nat Commun 16(1):8581 PMID: 41022720
- 3. Liziczai M et al.. 2025. Structural basis for metal ion transport by the human SLC11 proteins DMT1 and NRAMP1.. Nat Commun 16(1):761 PMID: 39824808
- 4. Spath NB et al.. 2019. Manganese-enhanced MRI of the myocardium.. Heart 105(22):1695-1700 PMID: 31337670
- 5. Bearer EL et al.. 2022. Studying Axonal Transport in the Brain by Manganese-Enhanced Magnetic Resonance Imaging (MEMRI).. Methods Mol Biol 2431:111-142 PMID: 35412274
- 6. Luo T et al.. 2023. Fate and Transport of Pharmaceuticals in Iron and Manganese Binary Oxide Coated Sand Columns.. Environ Sci Technol 57(1):214-221 PMID: 36469013
- 7. Ye Q et al.. 2017. Influence of iron metabolism on manganese transport and toxicity.. Metallomics 9(8):1028-1046 PMID: 28620665
- 8. Li C et al.. 2026. Shielding effect-induced enhancement of chloride ion transport in manganese oxide mixed matrix membranes for efficient separation.. Water Res 292:125273 PMID: 41478174
