GO:0033212 iron import into cell: Transport Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0033212 iron import into cell describes the directed movement of iron ions from outside a cell into the cytoplasmic compartment, either by transport across the plasma membrane or by endocytosis.
• Iron import is essential for heme synthesis, iron-sulfur cluster assembly, mitochondrial respiration, and DNA synthesis, and its dysregulation is linked to cancer, neurodegeneration, and inflammatory disease [1,8].
• Key protein players include transferrin receptor 1 (TFRC), divalent metal transporter 1 (SLC11A2/DMT1), ferroportin (SLC40A1), and the endosomal STEAP3 metalloreductase.
• Mitochondrial iron handling intersects with iron import through proteins such as DELE1, which senses mitochondrial iron status and signals to the integrated stress response.
• Iron import influences cell death programs: iron-activated ROS can drive pyroptosis in melanoma via Tom20 signaling, and iron overload promotes ferroptosis, which can be modulated by SIRT3 and SLC7A11.
• CRISPR knockout, point-mutation, knock-in, and overexpression models enable causal dissection of iron import genes in cancer, metabolic, and neurodegenerative contexts.
Description
Iron is an indispensable trace element that serves as a cofactor for enzymes involved in oxygen transport, oxidative phosphorylation, DNA replication, and heme biosynthesis. Because free iron can catalyze reactive oxygen species (ROS) generation, cells must tightly regulate the directed movement of iron ions from the extracellular environment into the cytoplasmic compartment, a process formally annotated as GO:0033212 iron import into cell. This biological process encompasses both transport across the plasma membrane and endocytic routes that deliver iron to the cytoplasm. Understanding GO:0033212 is central to iron biology because defects in iron import underlie disorders ranging from anemia of inflammation to hereditary hemochromatosis, and because cancer cells frequently reprogram iron uptake to support proliferation. The process also intersects with cell death pathways: iron-activated ROS signaling can promote pyroptosis in melanoma cells, and mitochondrial iron-responsive pathways regulated by DELE1 couple iron status to the integrated stress response. In this article, we synthesize the QuickGO definition of GO:0033212 with verified PubMed literature to provide a research-grade overview of its mechanism, key genes, disease relevance, and experimental models.
iron import into cell At A Glance
| GO ID | GO:0033212 |
|---|---|
| GO term | iron import into cell |
| Ontology | biological_process |
| Synonym | ferrous ion import; ferrous iron import; ferrous iron uptake; iron assimilation |
| Definition | The directed movement of iron ions from outside of a cell into the cytoplasmic compartment, via transport across the plasma membrane or via endocytosis. |
| Major function | Delivery of iron to the cytoplasm for heme synthesis, iron-sulfur cluster assembly, mitochondrial respiration, and DNA synthesis. |
| Key transporters | TFRC, SLC11A2/DMT1, SLC40A1/ferroportin, STEAP3, and endosomal recycling machinery. |
| Cellular locations | Plasma membrane, endosomal membrane, endocytic vesicles, and cytoplasm. |
| Disease links | Cancer, neurodegeneration, iron overload disorders, and inflammatory disease [1,8]. |
What Is GO:0033212?
GO:0033212 iron import into cell is defined by QuickGO as the directed movement of iron ions from outside of a cell into the cytoplasmic compartment, which may occur via transport across the plasma membrane or via endocytosis. In practice, this includes the reduction of ferric iron (Fe3+) to ferrous iron (Fe2+) at the cell surface or in endosomes, the translocation of iron across lipid bilayers by transporters such as SLC11A2/DMT1, and the endocytic uptake of iron-loaded transferrin via TFRC followed by release of iron into the cytoplasm. The term is synonymous with ferrous ion import, ferrous iron import, ferrous iron uptake, and iron assimilation, and it is a biological_process in the Gene Ontology.
Why Is iron import into cell Important in Cell Biology?
Iron import into cell (GO:0033212) is a foundational process because virtually every proliferating cell requires iron for ribonucleotide reductase, mitochondrial electron transport, and heme-dependent enzymes. Its dysregulation contributes to cancer progression, where tumor cells often increase iron uptake to sustain growth, and to cell death programs such as ferroptosis and pyroptosis that are modulated by iron-dependent ROS [2,7]. Moreover, mitochondrial iron-responsive signaling through DELE1 links iron import to the integrated stress response, connecting iron homeostasis to broader cellular stress adaptation.
• Provides iron for heme biosynthesis and iron-sulfur cluster assembly in mitochondria and cytosol.
• Supports DNA synthesis via ribonucleotide reductase, which requires iron.
• Is frequently upregulated in cancer to meet high proliferative demand for iron.
• Contributes to ferroptosis, an iron-dependent form of regulated cell death.
• Can trigger pyroptosis through iron-activated ROS signaling in melanoma cells.
• Links to mitochondrial stress signaling via DELE1 and the integrated stress response.
• Is relevant to asbestos-induced pathology, where iron contributes to oxidative damage.
• Is conserved across kingdoms, including symbiotic iron import in plant nodules.
• Represents a therapeutic target for iron chelation and transporter inhibition [1,8].
• Is modulated by mitochondrial glutathione homeostasis and SIRT3-dependent mitophagy [4,7].
What Happens During iron import into cell?
Transferrin-mediated endocytosis
In simple terms: Cells grab iron-carrying transferrin from outside and pull it inside in bubbles called endosomes.
The canonical route of iron import begins when diferric transferrin binds transferrin receptor 1 (TFRC) at the plasma membrane, triggering clathrin-mediated endocytosis. Inside acidified endosomes, iron is released from transferrin and reduced by STEAP3, then transported across the endosomal membrane into the cytoplasm by SLC11A2/DMT1. This pathway delivers iron to the cytoplasmic labile iron pool, where it becomes available for heme synthesis, iron-sulfur cluster assembly, and storage in ferritin.
Non-transferrin-bound iron uptake
In simple terms: When transferrin is saturated, cells can still take up free iron through other transporters.
Under conditions of iron overload, non-transferrin-bound iron (NTBI) can be imported via transporters such as SLC11A2/DMT1 and ZIP family proteins at the plasma membrane. This route requires reduction of Fe3+ to Fe2+ by surface reductases before transport. NTBI uptake is particularly relevant in hereditary hemochromatosis and in cancer cells that upregulate iron import machinery to support proliferation [1,8].
Mitochondrial iron sensing and DELE1 signaling
In simple terms: Mitochondria monitor iron levels and send a distress signal when iron is low or unbalanced.
Mitochondria are major iron consumers, and their iron status is monitored by pathways involving DELE1, which is cleaved and signals to the integrated stress response when mitochondrial iron homeostasis is perturbed. This mitochondrial iron-responsive pathway connects iron import into the cell with broader stress adaptation and can influence cell survival decisions. Autoregulatory control of mitochondrial glutathione homeostasis further integrates iron handling with redox balance.
Iron-dependent cell death execution
In simple terms: Too much iron inside a cell can trigger specific self-destruction programs.
Iron imported into the cytoplasm can participate in Fenton chemistry to generate ROS, which in melanoma cells promotes Tom20-dependent pyroptosis. Iron overload also sensitizes cells to ferroptosis, a lipid peroxidation-driven death program that can be modulated by SIRT3 and SLC7A11. These findings position GO:0033212 as a determinant of cell fate under oxidative stress [2,7].
Evolutionary conservation and symbiotic iron import
In simple terms: Plants also import iron into specialized compartments during symbiosis.
Iron import is not limited to animal cells; in Medicago truncatula, Ferroportin2 mediates iron import into nodule symbiosomes, highlighting conserved mechanisms of directed iron movement across membranes. This conservation underscores the fundamental importance of GO:0033212 across kingdoms.
Key Genes Involved in GO:0033212 iron import into cell
The following genes and proteins are experimentally implicated in iron import into cell (GO:0033212) and related iron homeostasis pathways.
| Gene | Major Role | Research Relevance |
|---|---|---|
| TFRC | Transferrin receptor 1; binds diferric transferrin and mediates endocytic iron uptake | Target for studying endocytic iron import and cancer proliferation [1,8] |
| SLC11A2 (DMT1) | Divalent metal transporter 1; transports Fe2+ across plasma and endosomal membranes | Key transporter for non-transferrin-bound iron and endosomal iron release |
| SLC40A1 (ferroportin) | Iron exporter; also mediates iron import into symbiosomes in plants | Studied in iron overload and symbiotic iron transport |
| STEAP3 | Endosomal metalloreductase; reduces Fe3+ to Fe2+ for transport | Required for efficient endosomal iron release |
| DELE1 | Mitochondrial iron-responsive signaling protein | Links mitochondrial iron status to integrated stress response |
| SIRT3 | Mitochondrial deacetylase; regulates mitophagy and ferroptosis sensitivity | Modulates iron-dependent cell death in glioblastoma |
| SLC7A11 | Cystine/glutamate antiporter; influences ferroptosis via glutathione | Target for ferroptosis modulation in cancer |
| Tom20 | Mitochondrial import receptor; involved in iron-activated ROS signaling | Mediates pyroptosis in melanoma cells |
| Ferritin (FTL/FTH1) | Iron storage protein; buffers cytoplasmic iron | Readout of iron import and storage balance |
| Hepcidin (HAMP) | Systemic iron regulator; controls ferroportin stability | Links systemic iron homeostasis to cellular import |
| DMT1 splice variants | Tissue-specific iron transporters | Studied for isoform-specific import functions |
| ZIP8/ZIP14 | Metal transporters capable of iron uptake | Candidate NTBI importers |
| Transferrin (TF) | Iron carrier in serum; delivers iron to TFRC | Essential for endocytic iron import |
| HFE | Hemochromatosis protein; regulates TFRC-mediated uptake | Disease gene for hereditary hemochromatosis |
| Hephaestin | Ferroxidase; aids iron export and recycling | Indirectly affects iron import balance |
| NRF2 | Transcription factor; regulates antioxidant and iron genes | Modulates iron import under oxidative stress |
| IRP1/IRP2 (ACO1/IREB2) | Iron regulatory proteins; post-transcriptional control of iron genes | Master regulators of iron import and storage |
| Mitochondrial carriers (SLC25A37/38) | Mitochondrial iron import proteins | Deliver iron to mitochondrial compartments |
How Is iron import into cell Regulated?
Iron import into cell (GO:0033212) is regulated at multiple levels. Systemically, the hormone hepcidin controls the stability of the exporter ferroportin, thereby influencing iron availability for import. At the cellular level, iron regulatory proteins IRP1 and IRP2 bind iron-responsive elements in mRNAs encoding TFRC, ferritin, and other iron genes to coordinate import with storage and export. Mitochondrial iron status is monitored by DELE1, which signals to the integrated stress response when iron homeostasis is perturbed. Additionally, mitochondrial glutathione homeostasis is autoregulated, integrating redox balance with iron handling. In cancer, oncogenic signaling and tumor microenvironment factors can upregulate iron import to support proliferation.
iron import into cell and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TFRC | Cancer proliferation and iron uptake | CRISPR knockout in cancer cell lines; overexpression for gain-of-function |
| SLC11A2 (DMT1) | Iron overload and endosomal iron transport | Point-mutation knock-in to test transport activity |
| DELE1 | Mitochondrial stress and neurodegeneration | Knockout and tagged knock-in for stress signaling |
| SIRT3 | Glioblastoma ferroptosis sensitivity | Knockout and overexpression in glioblastoma models |
| SLC7A11 | Ferroptosis and redox balance | Knockout to sensitize cells to ferroptosis |
Iron import in cancer
Cancer cells frequently reprogram iron metabolism to sustain rapid proliferation, and increased iron import via TFRC and SLC11A2 supports tumor growth. Iron-dependent ROS can also drive specific cell death programs; in melanoma, iron-activated ROS signaling promotes Tom20-dependent pyroptosis. In glioblastoma, targeting SIRT3 sensitizes cells to ferroptosis by promoting mitophagy and inhibiting SLC7A11, linking iron import to therapeutic vulnerability. These findings suggest that iron import genes are candidate targets for cancer therapy.
Neurodegeneration and iron overload
Dysregulated iron import and accumulation are implicated in neurodegenerative conditions and iron overload disorders. Mitochondrial iron-responsive pathways involving DELE1 may contribute to neuronal stress responses when iron homeostasis is disrupted. Autoregulatory control of mitochondrial glutathione homeostasis further highlights how iron and redox balance intersect in disease.
Inflammatory and environmental disease
Asbestos exposure is associated with iron-driven oxidative damage, and iron import mechanisms may modulate cellular responses to such environmental insults. Systemic iron regulation by hepcidin and ferroportin influences inflammatory anemia and iron overload states.
Symbiotic and plant iron import
In Medicago truncatula, Ferroportin2 mediates iron import into nodule symbiosomes, demonstrating that GO:0033212-like processes are relevant to plant-microbe symbiosis and agricultural biology.
From iron import into cell-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is TFRC required for iron import and proliferation? | CRISPR knockout of TFRC in cancer cell lines |
| Does a point mutation in SLC11A2 alter transport activity? | Point-mutation knock-in of SLC11A2 |
| Can DELE1 signaling be monitored in live cells? | Tagged knock-in of DELE1 with fluorescent reporter |
| Does SIRT3 overexpression protect against ferroptosis? | Overexpression of SIRT3 in glioblastoma cells |
| Is SLC7A11 a determinant of ferroptosis sensitivity? | CRISPR knockout of SLC7A11 |
| Does ferroportin mediate iron import in symbiosomes? | Heterologous expression in plant nodule models |
How to Study the iron import into cell Process
| Method | What It Measures | Typical Application |
|---|---|---|
| 55Fe uptake assay | Rate of iron import into cells | Comparing wild-type and knockout cells |
| ICP-MS | Total cellular iron content | Quantifying iron loading after perturbation |
| RNA-seq | Transcriptional changes in iron genes | Identifying iron import signatures |
| Proteomics | Protein abundance of transporters | Validating CRISPR knockout effects |
| Fluorescence microscopy | Subcellular localization of iron transporters | Tracking endosomal iron release |
| Lipid peroxidation assay | Ferroptosis induction | Testing SIRT3/SLC7A11 modulation |
| ROS detection | Oxidative stress levels | Linking iron import to pyroptosis |
| CRISPR library screening | Genes required for iron import | Identifying novel regulators |
Measuring iron import flux
Iron import can be quantified using radiolabeled iron (e.g., 55Fe) uptake assays, fluorescent iron probes such as calcein-AM, and ICP-MS to measure total cellular iron. These methods are used to compare wild-type and CRISPR-edited cells to determine the contribution of specific transporters.
Transcriptomic and proteomic profiling
RNA-seq and proteomics can reveal changes in iron import genes such as TFRC, SLC11A2, and ferritin following genetic perturbation [1,8]. Bioinformatics analysis of iron-related gene signatures helps identify regulatory networks and candidate drivers.
Imaging and subcellular localization
Fluorescence microscopy with tagged transporters and endosomal markers can visualize endocytic iron uptake and trafficking. Mitochondrial iron sensors such as DELE1 can be imaged using knock-in reporters.
Cell death and redox assays
Ferroptosis and pyroptosis can be assessed using lipid peroxidation probes, ROS sensors, and caspase/gasdermin activation assays [2,7]. These readouts link iron import to cell fate decisions [2,7].
How CRISPR Can Be Used to Study GO:0033212 iron import into cell
Knockout
CRISPR knockout of iron import genes such as TFRC, SLC11A2, or SLC7A11 can abolish or reduce iron uptake, enabling causal tests of their requirement for proliferation and survival [1,7,8]. Knockout models are also used to validate ferroptosis sensitivity.
Point Mutation
Point-mutation knock-in can model disease-associated variants in iron transporters and assess their impact on transport activity and cellular iron homeostasis. This approach is valuable for dissecting structure-function relationships in SLC11A2 and related proteins.
Knock-in
Tagged knock-in of genes such as DELE1 allows real-time monitoring of mitochondrial iron-responsive signaling and stress pathway activation. Knock-in reporters can also track endosomal iron release dynamics.
Overexpression
Overexpression of iron import genes or regulators like SIRT3 can test gain-of-function effects on iron accumulation, ferroptosis resistance, and tumor growth [7,8]. Overexpression models complement knockout studies to establish sufficiency.
How EDITGENE Supports iron import into cell Research
Researchers studying iron import into cell-related genes often need to determine whether a candidate gene is causally involved in iron uptake, whether a specific variant alters transporter function, or whether overexpression is sufficient to drive iron-dependent phenotypes. EDITGENE provides end-to-end CRISPR services to generate precisely engineered cell models that answer these questions.
Contact EDITGENE today to design your custom CRISPR model for iron import into cell research.
Frequently Asked Questions About iron import into cell
What is GO:0033212 iron import into cell?
GO:0033212 is a Gene Ontology biological process term describing the directed movement of iron ions from outside a cell into the cytoplasmic compartment, via plasma membrane transport or endocytosis.
What genes are involved in iron import into cell?
Key genes include TFRC, SLC11A2 (DMT1), SLC40A1 (ferroportin), STEAP3, DELE1, SIRT3, and SLC7A11, among others [1,3,6,7].
How is iron imported into cells?
Iron can be imported via transferrin receptor-mediated endocytosis or via transporters such as DMT1 that move Fe2+ across membranes.
Why is iron import important for cancer?
Cancer cells often upregulate iron import to support proliferation, and iron-dependent ROS can influence cell death pathways such as ferroptosis and pyroptosis [2,7,8].
What is the role of DELE1 in iron import?
DELE1 is part of a mitochondrial iron-responsive pathway that signals to the integrated stress response when mitochondrial iron homeostasis is perturbed.
How can CRISPR be used to study iron import?
CRISPR knockout, point-mutation knock-in, tagged knock-in, and overexpression models allow causal testing of iron import genes in cellular assays [1,7,8].
What diseases are linked to iron import?
Iron import dysregulation is linked to cancer, neurodegeneration, iron overload disorders, and inflammatory conditions [1,5,8].
What methods measure iron import?
Radiolabeled iron uptake assays, ICP-MS, fluorescent probes, RNA-seq, proteomics, and imaging are commonly used [1,8].
Is iron import conserved in plants?
Yes, Ferroportin2 mediates iron import into nodule symbiosomes in Medicago truncatula, showing conservation across kingdoms.
How does SIRT3 affect iron-dependent cell death?
Targeting SIRT3 sensitizes glioblastoma cells to ferroptosis by promoting mitophagy and inhibiting SLC7A11.
Conclusion
GO:0033212 iron import into cell is a central biological process that delivers iron to the cytoplasm through endocytic and transport routes, supporting essential metabolic functions while contributing to oxidative stress and cell death when dysregulated. Its relevance spans cancer, neurodegeneration, iron overload, and even plant symbiosis, making it a rich area for mechanistic and therapeutic research [1,6,8]. CRISPR-based models, combined with iron flux assays and multi-omics, provide powerful tools to dissect the genes and pathways controlling iron import [1,7,8].
References
- 1. Dutt S et al.. 2022. Molecular Mechanisms of Iron and Heme Metabolism.. Annu Rev Nutr 42:311-335 PMID: 35508203
- 2. Zhou B et al.. 2018. Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis.. Cell Res 28(12):1171-1185 PMID: 30287942
- 3. Sekine Y et al.. 2023. A mitochondrial iron-responsive pathway regulated by DELE1.. Mol Cell 83(12):2059-2076.e6 PMID: 37327776
- 4. Liu Y et al.. 2023. Autoregulatory control of mitochondrial glutathione homeostasis.. Science 382(6672):820-828 PMID: 37917749
- 5. Ghio AJ et al.. 2023. Asbestos and Iron.. Int J Mol Sci 24(15) PMID: 37569765
- 6. Escudero V et al.. 2020. Medicago truncatula Ferroportin2 mediates iron import into nodule symbiosomes.. New Phytol 228(1):194-209 PMID: 32367515
- 7. Li X et al.. 2024. Targeting SIRT3 sensitizes glioblastoma to ferroptosis by promoting mitophagy and inhibiting SLC7A11.. Cell Death Dis 15(2):168 PMID: 38395990
- 8. Torti SV et al.. 2025. Iron and Cancer.. Adv Exp Med Biol 1480:271-289 PMID: 40603797
