GO:0098711 iron ion import across plasma membrane: Transport Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0098711 describes the directed movement of iron ions from outside a cell, across the plasma membrane, and into the cytosol.
• Iron import across the plasma membrane is essential for cellular iron homeostasis and is mediated by dedicated transporters and carrier proteins in bacteria, fungi, plants, and animals [2, 3, 7].
• In yeast, mitochondrial carrier proteins Mrs3p and Mrs4p mediate iron transport across the inner mitochondrial membrane, a process related to but distinct from plasma membrane import.
• The bacterial iron-catecholate transporter Fiu imports substrates via a two-step mechanism, illustrating structural diversity in microbial iron uptake systems.
• Superoxide-dependent iron uptake can occur through anion exchange protein 2 (AE2), revealing a non-canonical route for iron entry into cells.
• Disruption of iron import across the plasma membrane contributes to developmental toxicity, microbial pathogenesis, and metal homeostasis disorders [1, 2].
Description
Iron is an essential trace element required for oxygen transport, electron transfer, DNA synthesis, and many enzymatic reactions. Because free iron can catalyze harmful radical reactions, its uptake across the plasma membrane is tightly controlled. GO:0098711, iron ion import across plasma membrane, defines the directed movement of iron ions from outside a cell, across the plasma membrane, and into the cytosol. This process is the first committed step in cellular iron acquisition and is conserved from bacteria to humans. In sulfate-reducing bacteria, genomic analyses have revealed specialized iron acquisition systems that operate in microaerophilic environments. In yeast, mitochondrial carrier proteins Mrs3p and Mrs4p mediate iron transport across the inner mitochondrial membrane, a related but distinct process that informs our understanding of iron trafficking. In mammals, superoxide-dependent iron uptake through anion exchange protein 2 (AE2) provides an additional route for iron entry. Understanding GO:0098711 is therefore central to iron biology, host-pathogen interactions, and diseases of iron overload or deficiency. Researchers studying this term need reliable models to dissect the molecular players, regulation, and physiological consequences of plasma membrane iron import.
iron ion import across plasma membrane At A Glance
| GO ID | GO:0098711 |
|---|---|
| GO term | iron ion import across plasma membrane |
| Ontology | biological_process |
| Synonym | ferrous ion import into cell; ferrous iron import across plasma membrane; ferrous iron import into cell; iron import into cell; iron ion import into cell |
| Major function | Directed transport of iron ions from the extracellular space across the plasma membrane into the cytosol |
| Cellular location | Plasma membrane |
| Directionality | Import (extracellular to intracellular) |
| Substrate | Iron ions (ferrous iron, Fe2+) |
| Taxonomic range | Bacteria, fungi, plants, animals |
What Is GO:0098711?
GO:0098711 (iron ion import across plasma membrane) is a biological process defined as the directed movement of iron ions from outside of a cell, across the plasma membrane, and into the cytosol. It includes the transport of ferrous iron (Fe2+) and related iron species into the cell, and is synonymous with ferrous ion import into cell, ferrous iron import across plasma membrane, ferrous iron import into cell, iron import into cell, and iron ion import into cell. This term specifically covers import across the plasma membrane, distinguishing it from intracellular iron transport steps such as mitochondrial iron uptake.
Why Is iron ion import across plasma membrane Important in Cell Biology?
Iron ion import across the plasma membrane is the gateway for cellular iron acquisition and is essential for processes ranging from respiration and DNA synthesis to host-pathogen interactions. In sulfate-reducing bacteria, iron acquisition systems are critical for survival in microaerophilic environments and influence biogeochemical cycling. In yeast, iron transport across mitochondrial membranes by Mrs3p/Mrs4p is required for iron-sulfur cluster biogenesis and mitochondrial function. In mammals, superoxide-dependent iron uptake via AE2 contributes to iron loading in the lung and other tissues. Disruption of iron import can cause developmental toxicity, as shown in zebrafish embryos exposed to environmental contaminants. Because iron is both essential and toxic, its import is tightly regulated, and defects in this process are linked to anemia, iron overload, neurodegeneration, and cancer. Studying GO:0098711 therefore provides mechanistic insight into metal homeostasis and identifies targets for therapeutic intervention.
• Iron import across the plasma membrane is the first step in cellular iron acquisition and is required for cell growth and proliferation.
• In bacteria, iron acquisition systems are virulence factors and are essential for colonization of host tissues.
• In yeast, mitochondrial iron transport by Mrs3p/Mrs4p supports iron-sulfur cluster assembly and respiratory function.
• Superoxide-dependent iron uptake through AE2 represents an alternative import route relevant to lung iron overload.
• Disruption of iron import can cause developmental toxicity and malformations in zebrafish embryos.
• Iron import is a potential target for antimicrobial therapy because pathogens depend on host iron.
• Dysregulated iron import contributes to cancer cell proliferation and metastasis.
• Iron import defects are linked to anemia and iron-refractory iron deficiency.
• Excess iron import can promote oxidative stress and neurodegeneration.
• Understanding iron import mechanisms aids in designing chelation therapies and metal-based drugs.
What Happens During iron ion import across plasma membrane?
Substrate recognition and binding at the cell surface
In simple terms: The cell first grabs iron from the outside environment using specialized proteins.
Iron in the extracellular space is often bound to siderophores, transferrin, or other carriers. In bacteria, the iron-catecholate transporter Fiu recognizes and binds its substrate with high specificity, as revealed by structural studies showing a two-step import mechanism. In sulfate-reducing bacteria, genomic analyses have identified multiple iron acquisition systems that function in microaerophilic conditions. This initial binding step ensures that iron is captured efficiently despite its low solubility.
Transport across the plasma membrane
In simple terms: The bound iron is then moved through the membrane into the cell.
Following recognition, iron ions are translocated across the plasma membrane into the cytosol. The bacterial Fiu transporter imports iron-catecholate complexes via a two-step mechanism involving conformational changes. In mammals, superoxide-dependent iron uptake through anion exchange protein 2 (AE2) provides an additional import route, where superoxide reduces ferric iron to ferrous iron, which is then transported. This step is energy-dependent in many systems and is tightly regulated to prevent iron overload.
Intracellular iron trafficking and utilization
In simple terms: Once inside, iron is delivered to where it is needed, such as mitochondria.
After import into the cytosol, iron is distributed to intracellular compartments. In yeast, the mitochondrial carrier proteins Mrs3p and Mrs4p mediate iron transport across the inner mitochondrial membrane, a process required for iron-sulfur cluster and heme biosynthesis. The mitochondrial carrier Rim2 co-imports pyrimidine nucleotides and iron, linking iron transport to nucleotide metabolism. These downstream trafficking steps are distinct from plasma membrane import but are functionally coupled to it.
Regulation and feedback control
In simple terms: The cell adjusts how much iron it takes in based on its needs.
Iron import across the plasma membrane is regulated at multiple levels. In bacteria, iron acquisition genes are controlled by iron-responsive regulators such as Fur, which repress transcription when iron is abundant. In plants, ATP-binding cassette (ABC) transporters contribute to metal homeostasis under abiotic and biotic stresses. In mammals, iron uptake is post-transcriptionally regulated by iron regulatory proteins (IRPs) that bind to iron-responsive elements (IREs) in mRNAs encoding transport proteins. This feedback ensures that iron import matches cellular demand and prevents toxicity.
Copper import as a comparative model
In simple terms: Studying how cells import copper helps us understand iron import.
The reconstitution of a thermophilic Cu+ importer in vitro revealed intrinsic high-affinity slow transport driving accumulation of an essential metal ion. This work provides a framework for understanding how metal ions like iron are imported across the plasma membrane with high affinity and specificity. Comparative studies of copper and iron import highlight shared principles of metal transport, including energy coupling and conformational cycling.
Key Genes Involved in GO:0098711 iron ion import across plasma membrane
The following genes and proteins are experimentally implicated in iron ion import across the plasma membrane or in related iron transport processes.
| Gene | Major Role | Research Relevance |
|---|---|---|
| Fiu (bacterial) | Iron-catecholate transporter that imports substrates via a two-step mechanism | Structural and mechanistic studies of bacterial iron uptake |
| Mrs3p (yeast) | Mitochondrial carrier protein mediating iron transport across the inner mitochondrial membrane | Model for mitochondrial iron import and iron-sulfur cluster biogenesis |
| Mrs4p (yeast) | Mitochondrial carrier protein mediating iron transport across the inner mitochondrial membrane | Functional partner of Mrs3p in mitochondrial iron transport |
| Rim2 (yeast) | Mitochondrial carrier that co-imports pyrimidine nucleotides and iron | Links iron transport to nucleotide metabolism |
| AE2 (human) | Anion exchange protein 2 mediating superoxide-dependent iron uptake | Non-canonical iron import route in lung and other tissues |
| ABC transporters (plant) | ATP-binding cassette transporters involved in metal homeostasis | Roles in abiotic and biotic stress responses |
| Cu+ importer (thermophilic) | High-affinity copper importer | Comparative model for metal ion import mechanisms |
| Sulfate-reducing bacteria iron acquisition genes | Genomic systems for iron acquisition in microaerophilic environments | Microbial iron uptake and biogeochemistry |
| Zebrafish iron transport genes | Genes affected by 6PPD and 6PPDQ developmental toxicity | Developmental toxicity and iron homeostasis |
| Ferroportin (SLC40A1) | Iron exporter (opposite direction) | Contrasts with import for understanding iron flux |
| DMT1 (SLC11A2) | Divalent metal transporter 1 | Major mammalian iron importer at plasma membrane |
| Transferrin receptor 1 (TFRC) | Mediates transferrin-bound iron uptake | Endocytic iron import pathway |
| Ferritin (FTL/FTLH) | Iron storage protein | Buffers cytosolic iron after import |
| IRP1/IRP2 (ACO1/IREB2) | Iron regulatory proteins | Post-transcriptional regulation of iron import genes |
| Hepcidin (HAMP) | Systemic iron regulator | Controls iron export and availability |
| Fur (bacterial) | Iron-responsive repressor | Regulates bacterial iron acquisition genes |
| ZIP transporters | Zinc/iron transporters | Broad metal ion import functions |
How Is iron ion import across plasma membrane Regulated?
Iron ion import across the plasma membrane is regulated at transcriptional, post-transcriptional, and post-translational levels. In bacteria, the ferric uptake regulator (Fur) represses iron acquisition genes when intracellular iron is sufficient, as reviewed in genomic analyses of sulfate-reducing bacteria. In plants, ATP-binding cassette (ABC) transporters contribute to metal homeostasis under abiotic and biotic stresses, indicating stress-responsive regulation. In mammals, the iron regulatory protein/iron-responsive element (IRP/IRE) system controls the stability and translation of mRNAs encoding iron import proteins such as DMT1 and TFRC. Superoxide-dependent iron uptake via AE2 is influenced by oxidative stress. Additionally, mitochondrial iron transport by Mrs3p/Mrs4p is regulated by the mitochondrial carrier family and co-factor availability [3, 6]. These layered controls ensure that iron import matches cellular demand and prevents iron-mediated toxicity.
iron ion import across plasma membrane and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| AE2 (SLC4A2) | Lung iron overload and oxidative stress | Knockout or point-mutation in human cell lines |
| Mrs3p/Mrs4p | Mitochondrial iron-sulfur cluster deficiency | Yeast knockout and rescue with tagged knock-in |
| Rim2 | Nucleotide and iron co-transport defects | Yeast knockout and overexpression |
| Fiu | Bacterial iron acquisition and pathogenesis | Bacterial knockout and complementation |
| Zebrafish iron transport genes | Developmental toxicity from environmental contaminants | Zebrafish knockout and overexpression |
Iron overload and oxidative stress
Excessive iron import across the plasma membrane can lead to cytosolic iron accumulation, promoting reactive oxygen species (ROS) generation and oxidative damage. Superoxide-dependent iron uptake through AE2 has been implicated in lung iron overload and asbestos-related diseases. In zebrafish, exposure to 6PPD and its metabolite 6PPDQ induces developmental toxicity and altered iron-related phenotypes, highlighting the sensitivity of iron import pathways to environmental toxicants.
Microbial pathogenesis and host iron competition
Pathogenic bacteria rely on iron acquisition systems to obtain iron from host proteins. Genomic insights into sulfate-reducing bacteria reveal diverse iron acquisition strategies that operate in microaerophilic environments. The bacterial iron-catecholate transporter Fiu is a paradigm for understanding how pathogens import iron-catecholate complexes, which could inform antimicrobial drug design.
Mitochondrial dysfunction and iron-sulfur cluster disorders
Defects in mitochondrial iron transport, mediated by Mrs3p/Mrs4p and Rim2, impair iron-sulfur cluster biogenesis and mitochondrial respiration [3, 6]. These defects are linked to neurodegenerative diseases and sideroblastic anemia. Understanding plasma membrane iron import is essential because it supplies the cytosolic iron pool that feeds mitochondria.
Cancer and proliferative signaling
Cancer cells often upregulate iron import to support rapid proliferation. Although direct evidence for GO:0098711 in cancer is limited in the provided citations, the general principle that iron acquisition supports cell growth is well established. Targeting iron import pathways is an emerging therapeutic strategy.
From iron ion import across plasma membrane-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does a candidate gene mediate iron import across the plasma membrane? | Knockout cell lines followed by iron uptake assays |
| Does a specific mutation alter transport activity? | Point-mutation knock-in cell lines |
| Can a tagged transporter be visualized at the plasma membrane? | Tagged knock-in with fluorescent protein |
| Does overexpression increase iron import and cellular iron content? | Overexpression cell lines |
| Which genes regulate iron import under stress? | CRISPR library screening |
| What is the transcriptional response to iron availability? | RNA-seq after iron chelation or loading |
How to Study the iron ion import across plasma membrane Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radioactive iron uptake | Rate of iron import | Quantifying transport activity in knockout cells |
| RNA-seq | Transcriptional changes | Identifying iron-responsive genes [2, 5] |
| Proteomics | Protein abundance and interactions | Characterizing transporter complexes [3, 7] |
| Fluorescence microscopy | Subcellular localization | Visualizing tagged transporters [3, 6] |
| CRISPR library screening | Gene essentiality and fitness | Identifying regulators of iron import |
| Bioinformatics | Genomic and structural analysis | Predicting transporter function [2, 7] |
| In vitro reconstitution | Intrinsic transport kinetics | Measuring metal ion transport |
| Zebrafish developmental assays | Phenotypic toxicity | Assessing iron-related developmental defects |
Iron uptake assays
Radioactive or fluorescent iron isotopes (e.g., 55Fe, 59Fe) are used to measure iron import across the plasma membrane in live cells. These assays can be performed in knockout, point-mutation, or overexpression models to quantify transport activity [4, 7].
Transcriptomics and RNA-seq
RNA sequencing reveals changes in expression of iron import genes under different iron conditions or genetic perturbations. This approach has been used to study iron acquisition in sulfate-reducing bacteria and plant ABC transporters under stress.
Proteomics and interactomics
Mass spectrometry-based proteomics can identify proteins associated with iron transporters and quantify their abundance. This is useful for studying mitochondrial carrier proteins like Mrs3p/Mrs4p and the bacterial Fiu transporter.
Imaging and subcellular localization
Fluorescence microscopy with tagged transporters (e.g., GFP fusions) allows visualization of plasma membrane localization and trafficking. Tagged knock-in cell lines generated by CRISPR are ideal for such studies [3, 6].
How CRISPR Can Be Used to Study GO:0098711 iron ion import across plasma membrane
Knockout
CRISPR knockout cell lines are used to delete candidate iron import genes and measure the resulting changes in iron uptake, cellular iron content, and downstream phenotypes. For example, knocking out AE2 in human cells can test its role in superoxide-dependent iron uptake. Yeast knockouts of MRS3 and MRS4 have been used to study mitochondrial iron transport.
Point Mutation
Point-mutation knock-in models allow researchers to test the functional impact of specific amino acid changes in iron transporters. This is particularly useful for dissecting the two-step mechanism of bacterial Fiu or for modeling human mutations in iron transport genes.
Knock-in
Tagged knock-in cell lines, where a fluorescent or affinity tag is inserted into an endogenous iron transporter gene, enable real-time visualization and biochemical purification of the transporter. This approach has been applied to study mitochondrial carriers like Rim2 and Mrs3p/Mrs4p.
Overexpression
Overexpression of iron import genes can increase cellular iron uptake and reveal gain-of-function phenotypes. This is useful for studying the capacity of transporters like Fiu and for testing whether increased iron import drives proliferation or toxicity.
How EDITGENE Supports iron ion import across plasma membrane Research
Researchers studying iron ion import across plasma membrane-related genes often need to determine whether a candidate gene is causally involved in iron uptake, how specific mutations affect transport activity, and whether modulating expression alters cellular iron homeostasis. EDITGENE provides end-to-end CRISPR services to generate precisely engineered cell models for these questions.
Contact EDITGENE today to design your custom CRISPR model for iron ion import across plasma membrane research.
Frequently Asked Questions About iron ion import across plasma membrane
What is GO:0098711?
GO:0098711 is the Gene Ontology term for iron ion import across plasma membrane, defined as the directed movement of iron ions from outside a cell, across the plasma membrane, and into the cytosol.
What genes are involved in iron ion import across plasma membrane?
Genes include bacterial Fiu, yeast MRS3 and MRS4, yeast RIM2, human AE2 (SLC4A2), plant ABC transporters, and many others involved in iron acquisition [2, 3, 4, 5, 6, 7].
How is iron imported into cells?
Iron is imported by specialized transporters that recognize iron or iron complexes, translocate them across the plasma membrane, and release them into the cytosol [2, 7].
What is the difference between iron import and iron export?
Iron import moves iron into the cell across the plasma membrane, while iron export moves iron out of the cell; both are tightly regulated to maintain iron homeostasis.
Which diseases are linked to defects in iron import?
Defects in iron import are linked to iron overload, oxidative stress, mitochondrial dysfunction, developmental toxicity, and microbial pathogenesis [1, 2, 3, 4].
How can I study iron ion import across plasma membrane in the lab?
Common methods include radioactive iron uptake assays, RNA-seq, proteomics, fluorescence microscopy, and CRISPR knockout or overexpression models [3, 4, 7].
What is the role of mitochondria in iron transport?
Mitochondrial carrier proteins such as Mrs3p, Mrs4p, and Rim2 transport iron across the inner mitochondrial membrane for iron-sulfur cluster and heme synthesis [3, 6].
Can CRISPR be used to study iron import genes?
Yes, CRISPR knockout, point-mutation knock-in, tagged knock-in, and overexpression models are powerful tools to dissect iron import mechanisms [3, 4, 7].
What is superoxide-dependent iron uptake?
Superoxide-dependent iron uptake is a non-canonical route where superoxide reduces ferric iron to ferrous iron, which is then imported via anion exchange protein 2 (AE2).
Why is iron import important for bacteria?
Bacteria require iron for essential enzymes and often use specialized acquisition systems to obtain iron from hosts, making these systems virulence factors [2, 7].
Conclusion
GO:0098711, iron ion import across plasma membrane, is a fundamental biological process that governs cellular iron acquisition. Research across bacteria, yeast, plants, and mammals has revealed diverse transporters and regulatory mechanisms, from the bacterial Fiu transporter to yeast mitochondrial carriers and mammalian AE2 [2, 3, 4, 7]. Dysregulation of iron import contributes to developmental toxicity, iron overload, mitochondrial disorders, and microbial pathogenesis [1, 2, 3, 4]. Continued investigation using CRISPR-based models and advanced omics will further illuminate how cells balance iron uptake with toxicity, offering new therapeutic opportunities.
References
- 1. Zhang SY et al.. 2023. 6PPD and its metabolite 6PPDQ induce different developmental toxicities and phenotypes in embryonic zebrafish.. J Hazard Mater 455:131601 PMID: 37182464
- 2. Barton LL et al.. 2023. Genomic insight into iron acquisition by sulfate-reducing bacteria in microaerophilic environments.. Biometals 36(2):339-350 PMID: 35767096
- 3. Froschauer EM et al.. 2009. The yeast mitochondrial carrier proteins Mrs3p/Mrs4p mediate iron transport across the inner mitochondrial membrane.. Biochim Biophys Acta 1788(5):1044-50 PMID: 19285482
- 4. Ghio AJ et al.. 2003. Superoxide-dependent iron uptake: a new role for anion exchange protein 2.. Am J Respir Cell Mol Biol 29(6):653-60 PMID: 12791678
- 5. Dahuja A et al.. 2021. Role of ATP-binding cassette transporters in maintaining plant homeostasis under abiotic and biotic stresses.. Physiol Plant 171(4):785-801 PMID: 33280130
- 6. Froschauer EM et al.. 2013. The mitochondrial carrier Rim2 co-imports pyrimidine nucleotides and iron.. Biochem J 455(1):57-65 PMID: 23800229
- 7. Grinter R et al.. 2019. The structure of the bacterial iron-catecholate transporter Fiu suggests that it imports substrates via a two-step mechanism.. J Biol Chem 294(51):19523-19534 PMID: 31712312
- 8. Logeman BL et al.. 2018. Reconstitution of a thermophilic Cu(+) importer in vitro reveals intrinsic high-affinity slow transport driving accumulation of an essential metal ion.. J Biol Chem 293(40):15497-15512 PMID: 30131336
