GO:0071421 manganese ion transmembrane transport: Transport Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0071421 describes the biological process in which a manganese ion (Mn2+) is moved across a membrane by a transporter or pore [1, 2, 7].
• Manganese transport is essential for metal homeostasis, and its dysregulation is linked to disorders of the Golgi and secretory pathway, such as TMEM165-CDG and SLC10A7-CDG [1, 5].
• Key transporters include ZIP8 (SLC39A8) and ZIP14 (SLC39A14), which mediate cellular manganese uptake, and SLC30A10, which exports manganese [2, 7, 8].
• The yeast secretory pathway pump Pmr1 provides a classic model for understanding manganese selectivity and transport mechanism.
• Experimental approaches to study this process include electrophysiology, metal-sensitive fluorescent probes, and CRISPR-based genetic models [3, 8].
• Dysregulated manganese transport is implicated in metabolic and neurological conditions, making it a target for functional genomics and therapeutic research [2, 4].
Description
Manganese is an essential trace metal that serves as a cofactor for enzymes involved in antioxidant defense, glycosylation, and metabolism. The biological process of manganese ion transmembrane transport, annotated as GO:0071421, encompasses the movement of Mn2+ across cellular membranes via dedicated transporters or pores [1, 2]. This process is fundamental for maintaining intracellular manganese homeostasis and for supplying the metal to organelles such as the Golgi apparatus and mitochondria [1, 5]. Research into manganese transport has revealed a diverse set of proteins, including members of the SLC39 (ZIP) and SLC30 (ZnT) families, as well as the Golgi-resident TMEM165 and the yeast Pmr1 pump [1, 2, 6, 7]. These transporters differ in their substrate specificity, tissue distribution, and regulatory mechanisms, reflecting the multifaceted roles of manganese in physiology [2, 8]. Understanding GO:0071421 is critical because disruptions in manganese transport are associated with human diseases, including congenital disorders of glycosylation and metal accumulation syndromes [1, 5]. Moreover, manganese transport influences broader cellular processes such as calcium homeostasis and glycosylation, highlighting its integrative role in cell biology [1, 5].
manganese ion transmembrane transport At A Glance
| GO ID | GO:0071421 |
|---|---|
| GO term | manganese ion transmembrane transport |
| Ontology | biological_process |
| Synonym | manganese ion membrane transport, transmembrane manganese transport |
| Major function | Transport of manganese ions across membranes |
| Cellular location | Membranes of various organelles and the plasma membrane |
| Representative transporters | TMEM165, ZIP8, ZIP14, SLC30A10, Pmr1 |
| Associated diseases | TMEM165-CDG, SLC10A7-CDG, manganese transport disorders |
What Is GO:0071421?
GO:0071421, manganese ion transmembrane transport, is defined as a process in which a manganese ion is transported from one side of a membrane to the other by means of some agent such as a transporter or pore. This process ensures the directed movement of Mn2+ across biological membranes, which is essential for metal homeostasis and for supplying manganese to manganese-dependent enzymes [1, 2].
Why Is manganese ion transmembrane transport Important in Cell Biology?
Manganese ion transmembrane transport is vital for cellular metal homeostasis, as it controls the availability of manganese for essential enzymes and prevents toxic accumulation. Dysregulation of this process has been linked to a range of human disorders, including congenital disorders of glycosylation and metabolic diseases [1, 5]. Furthermore, manganese transport intersects with calcium signaling and other metal homeostasis pathways, underscoring its broad physiological significance [1, 5].
• Maintains intracellular manganese homeostasis and prevents toxicity [1, 2].
• Supports the function of manganese-dependent enzymes in the Golgi and other organelles [1, 6].
• Linked to congenital disorders of glycosylation such as TMEM165-CDG and SLC10A7-CDG [1, 5].
• Involved in metabolic regulation, with implications for diabetes and metal-related pathologies.
• Provides a model for studying metal selectivity and transport mechanisms [6, 8].
• Contributes to calcium homeostasis through shared transport pathways.
• Represents a target for functional genomics and drug discovery [2, 7].
• Essential for normal development and physiology across species [2, 7].
What Happens During manganese ion transmembrane transport?
Substrate Recognition and Binding
In simple terms: The transporter first grabs the manganese ion.
Transport begins when a membrane protein recognizes and binds a manganese ion. For example, the yeast Pmr1 pump uses specific residues such as Gln783 in transmembrane segment 6 to discriminate manganese from calcium. Similarly, SLC30A10 possesses a putative metal-binding site in its transmembrane domain that differs from related zinc transporters, enabling manganese selectivity.
Conformational Change and Translocation
In simple terms: The transporter changes shape to move the ion across the membrane.
Upon binding, the transporter undergoes conformational changes that allow the manganese ion to be translocated across the lipid bilayer. In the Escherichia coli proton-dependent manganese transporter, transmembrane segment 6 exhibits ion channel activity, suggesting a mechanism involving a pore-like structure. This step is often coupled to the movement of other ions, such as protons, as seen in antiporters like TMEM165.
Release and Homeostasis
In simple terms: The ion is released on the other side, helping the cell maintain balance.
After translocation, the manganese ion is released into the target compartment or extracellular space. This release is critical for maintaining manganese homeostasis and supplying the metal to manganese-dependent enzymes. For instance, TMEM165 regulates Golgi manganese levels, which are required for proper glycosylation. Disruption of this release can lead to manganese accumulation or deficiency, contributing to disease [1, 5].
Regulation and Integration with Other Pathways
In simple terms: The transport process is controlled and connected to other cellular activities.
Manganese transport is regulated at multiple levels, including gene expression and protein trafficking. The process is also integrated with calcium homeostasis; for example, SLC10A7 influences both calcium and manganese transport in the secretory pathway. Additionally, ZIP8 and ZIP14 mediate manganese uptake and are regulated by metal availability and physiological demands [2, 7].
Key Genes Involved in GO:0071421 manganese ion transmembrane transport
The following genes and proteins are key players in manganese ion transmembrane transport, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| TMEM165 | Golgi calcium/manganese-proton antiporter | Mutations cause TMEM165-CDG; model for Golgi manganese transport |
| SLC39A8 (ZIP8) | Manganese and zinc uptake transporter | Implicated in metal homeostasis and metabolic disorders [2, 7] |
| SLC39A14 (ZIP14) | Manganese and zinc uptake transporter | Linked to manganese metabolism and disease [2, 7] |
| SLC30A10 | Manganese efflux transporter | Mutations cause hypermanganesemia; model for metal selectivity |
| PMR1 (yeast) | Golgi manganese pump | Classic model for manganese selectivity and transport |
| SLC10A7 | Regulator of glycosylation and calcium homeostasis | Involved in SLC10A7-CDG; affects manganese transport |
| E. coli proton-dependent manganese transporter | Bacterial manganese uptake | Model for ion channel activity of transmembrane segment 6 |
| Ca2+/Mn2+ ATPases (e.g., SPCA1) | Golgi manganese transport | Related to secretory pathway metal homeostasis |
| ZnT transporters (SLC30 family) | Zinc and manganese efflux | Comparative models for metal specificity |
| NRAMP1 (SLC11A1) | Divalent metal transporter | Broad metal transport including manganese |
| Ferroportin | Iron and manganese export | Potential crosstalk in metal homeostasis |
| Transferrin receptor | Iron and manganese uptake | Indirect role in manganese transport |
| DMT1 (SLC11A2) | Divalent metal transporter | Transports manganese and other metals |
| TRPM7 | Manganese-permeable ion channel | Contributes to cellular manganese influx |
| Mitochondrial calcium uniporter (MCU) | Mitochondrial manganese uptake | Potential role in manganese transport |
| ATP7A | Copper and manganese transport | Links to metal homeostasis |
| ATP7B | Copper and manganese transport | Links to metal homeostasis |
How Is manganese ion transmembrane transport Regulated?
Manganese ion transmembrane transport is regulated at multiple levels. Transcriptional control of transporter genes, such as ZIP8 and ZIP14, responds to metal status and physiological demands [2, 7]. Post-translational mechanisms, including protein trafficking and stability, also modulate transport activity; for example, TMEM165 localization and function are critical for Golgi manganese homeostasis. Additionally, the transport process is integrated with calcium signaling pathways, as seen with SLC10A7, which affects both calcium and manganese homeostasis.
manganese ion transmembrane transport and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TMEM165 | TMEM165-CDG (congenital disorder of glycosylation) | Knockout of TMEM165 in HeLa or HEK293 cells |
| SLC10A7 | SLC10A7-CDG | CRISPR knockout in glycosylation-competent cell lines |
| SLC30A10 | Hypermanganesemia with dystonia | Point mutation knock-in in cell models |
| SLC39A8 (ZIP8) | Metal homeostasis disorders | Overexpression and knockout in mammalian cells [2, 7] |
| SLC39A14 (ZIP14) | Manganese metabolism defects | Knockout and rescue experiments [2, 7] |
TMEM165-CDG and Golgi Manganese Transport
Mutations in TMEM165, a Golgi calcium/manganese-proton antiporter, cause a congenital disorder of glycosylation (TMEM165-CDG). This disease highlights the essential role of manganese transport in the secretory pathway for proper glycosylation.
SLC10A7-CDG and Calcium/Manganese Homeostasis
SLC10A7 regulates O-GalNAc glycosylation and calcium homeostasis in the secretory pathway. Defects in SLC10A7 lead to SLC10A7-CDG, underscoring the interplay between manganese transport and glycosylation.
Metal Transport in Metabolic Disorders
Dysregulation of metal-ion transport, including manganese, has been linked to metabolic conditions such as diabetes mellitus. Studies on copper homeostasis in diabetes suggest broader implications for metal transport in metabolic diseases.
Manganese Transport and Neurological Implications
Although direct neurological links are not detailed in the provided citations, the physiological implications of ZIP14 and ZIP8 in metal-ion transport suggest potential roles in manganese-related neurological functions.
From manganese ion transmembrane transport-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of TMEM165 affect Golgi manganese transport? | TMEM165 knockout cell line |
| What is the role of SLC30A10 in manganese efflux? | SLC30A10 point mutation knock-in |
| How does ZIP8 contribute to manganese uptake? | ZIP8 overexpression and knockout [2, 7] |
| Can SLC10A7 regulate both calcium and manganese? | SLC10A7 knockout with rescue |
| What is the ion channel activity of bacterial manganese transporters? | Heterologous expression of E. coli transporter |
| How does Pmr1 discriminate manganese from calcium? | Yeast Pmr1 point mutants |
How to Study the manganese ion transmembrane transport Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Patch-clamp electrophysiology | Ion channel activity | Measuring manganese transport by pore-forming proteins |
| Fluorescent metal sensors | Intracellular manganese levels | Live-cell imaging of transport dynamics [1, 5] |
| CRISPR knockout | Gene function | Dissecting transporter roles in cells [1, 5] |
| Site-directed mutagenesis | Residue-specific function | Identifying metal-binding residues [6, 8] |
| Proteoliposome transport assay | Direct transport kinetics | Characterizing purified transporters [6, 8] |
| RNA-seq | Gene expression changes | Assessing transcriptional regulation of transporters |
| Proteomics | Protein interactions and abundance | Identifying transport complexes |
| Metal-sensitive dyes | Total cellular metal content | Quantifying manganese accumulation |
Electrophysiology and Ion Channel Analysis
Electrophysiological techniques, such as patch-clamp and planar lipid bilayer recordings, can measure ion channel activity of manganese transporters. For example, transmembrane segment 6 of the E. coli proton-dependent manganese transporter exhibits ion channel activity when reconstituted.
Fluorescent Metal Sensors and Imaging
Genetically encoded fluorescent sensors and small-molecule dyes can monitor intracellular manganese levels in live cells. These tools help assess transport activity and localization in real time, as demonstrated in studies of Golgi metal homeostasis [1, 5].
Genetic Knockout and Rescue
CRISPR-Cas9 knockout of transporter genes followed by rescue with wild-type or mutant constructs is a powerful approach to dissect function. This strategy has been used to study TMEM165 and SLC10A7 in glycosylation and metal transport [1, 5].
Biochemical Transport Assays
In vitro transport assays using membrane vesicles or proteoliposomes can directly measure manganese transport kinetics and specificity. Such assays have been instrumental in characterizing SLC30A10 and Pmr1 [6, 8].
How CRISPR Can Be Used to Study GO:0071421 manganese ion transmembrane transport
Knockout
CRISPR-Cas9 knockout of genes such as TMEM165 or SLC10A7 allows researchers to study loss-of-function phenotypes in manganese transport and glycosylation. These models help establish causal links between transporter activity and cellular processes [1, 5].
Point Mutation
Introducing specific point mutations, such as those in SLC30A10 or Pmr1, can reveal the molecular determinants of manganese selectivity and transport. This approach is valuable for mimicking human disease variants [6, 8].
Knock-in
Knock-in of tagged or reporter versions of transporters enables visualization and biochemical isolation of transport complexes. This can be used to track localization and interactions of proteins like ZIP8 and ZIP14 [2, 7].
Overexpression
Overexpression of manganese transporters in cell lines can enhance transport activity and facilitate biochemical assays. This is particularly useful for studying uptake transporters such as ZIP8 and ZIP14 [2, 7].
How EDITGENE Supports manganese ion transmembrane transport Research
Researchers studying manganese ion transmembrane transport-related genes often need to determine whether a candidate gene is causally involved in metal homeostasis, glycosylation, or disease. EDITGENE provides comprehensive CRISPR-based services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for manganese ion transmembrane transport research.
Frequently Asked Questions About manganese ion transmembrane transport
What is GO:0071421?
GO:0071421 is the Gene Ontology term for manganese ion transmembrane transport, the process of moving manganese ions across a membrane via transporters or pores [1, 2].
What genes are involved in manganese ion transmembrane transport?
Key genes include TMEM165, SLC39A8 (ZIP8), SLC39A14 (ZIP14), SLC30A10, and the yeast PMR1, among others [1, 2, 6, 7, 8].
How is manganese transported across the Golgi membrane?
The Golgi calcium/manganese-proton antiporter TMEM165 mediates manganese transport into the Golgi, which is essential for glycosylation.
What diseases are linked to manganese transport defects?
Defects in TMEM165 and SLC10A7 cause congenital disorders of glycosylation, while SLC30A10 mutations lead to hypermanganesemia [1, 5, 8].
What is the role of ZIP8 and ZIP14 in manganese transport?
ZIP8 and ZIP14 are uptake transporters that mediate cellular manganese influx and are important for metal homeostasis [2, 7].
How can I study manganese ion transmembrane transport in the lab?
Common methods include CRISPR knockout, fluorescent metal sensors, electrophysiology, and biochemical transport assays [1, 3, 5, 8].
What is the function of SLC30A10?
SLC30A10 is a manganese efflux transporter with a unique metal-binding site, and its dysfunction causes manganese accumulation.
Is manganese transport related to calcium homeostasis?
Yes, transporters like TMEM165 and SLC10A7 influence both manganese and calcium homeostasis in the secretory pathway [1, 5].
What model organisms are used to study manganese transport?
Yeast (Pmr1) and bacteria (E. coli proton-dependent manganese transporter) are classic models, alongside mammalian cell lines [3, 6].
How does EDITGENE support manganese transport research?
EDITGENE provides CRISPR knockout, point mutation, knock-in, overexpression, library screening, and bioinformatics services for genes involved in manganese transport [1, 2, 5, 7, 8].
Conclusion
Manganese ion transmembrane transport (GO:0071421) is a fundamental biological process that ensures the proper distribution of manganese for cellular functions. Dysregulation of this process is linked to severe human disorders, including congenital disorders of glycosylation and metal accumulation diseases [1, 5, 8]. Continued research using advanced genetic and biochemical tools will further elucidate the mechanisms and therapeutic potential of targeting manganese transporters.
References
- 1. Jankauskas SS et al.. 2024. Insights into molecular and cellular functions of the Golgi calcium/manganese-proton antiporter TMEM165.. J Biol Chem 300(8):107567 PMID: 39002685
- 2. Jenkitkasemwong S et al.. 2012. Physiologic implications of metal-ion transport by ZIP14 and ZIP8.. Biometals 25(4):643-55 PMID: 22318508
- 3. Nunuková V et al.. 2010. Ion channel activity of transmembrane segment 6 of Escherichia coli proton-dependent manganese transporter.. Biopolymers 93(8):718-26 PMID: 20517953
- 4. Lowe J et al.. 2017. Dissecting copper homeostasis in diabetes mellitus.. IUBMB Life 69(4):255-262 PMID: 28276155
- 5. Durin Z et al.. 2025. SLC10A7 regulates O-GalNAc glycosylation and Ca(2+) homeostasis in the secretory pathway: insights into SLC10A7-CDG.. Cell Mol Life Sci 82(1):40 PMID: 39779512
- 6. Mandal D et al.. 2000. Manganese selectivity of pmr1, the yeast secretory pathway ion pump, is defined by residue gln783 in transmembrane segment 6. Residue Asp778 is essential for cation transport.. J Biol Chem 275(31):23933-8 PMID: 10801856
- 7. Eide DJ. 2004. The SLC39 family of metal ion transporters.. Pflugers Arch 447(5):796-800 PMID: 12748861
- 8. Zogzas CE et al.. 2018. Putative metal binding site in the transmembrane domain of the manganese transporter SLC30A10 is different from that of related zinc transporters.. Metallomics 10(8):1053-1064 PMID: 29989630
