CISD1 (CDGSH Iron Sulfur Domain 1): Structure, Function, and Clinical Significance
A comprehensive biomedical overview of the CISD1 gene, encoding the mitochondrial protein mitoNEET, with emphasis on its role in iron-sulfur cluster binding, mitochondrial function, and disease associations.
Gene Information Card
| Symbol | CISD1 |
|---|---|
| Full Name | CDGSH iron sulfur domain 1 |
| Gene Type | protein coding |
| Chromosomal Location | 10q21.1 (GRCh38: chr10:58,267,407-58,289,583, minus strand) |
| NCBI Gene ID | 55847 ncbi.nlm.nih.gov/gene/55847 |
| Ensembl ID | ENSG00000153086 |
| UniProt ID | Q9NZ45 |
| OMIM ID | 611031 |
| HGNC ID | 24280 |
| Aliases | MitoNEET; C10orf72; CDGSH1; ZCD1 |
Description
CISD1 encodes a small (108 amino acid) mitochondrial outer membrane protein known as mitoNEET. It contains a CDGSH-type iron-sulfur (Fe-S) binding domain, which coordinates a [2Fe-2S] cluster. The protein is involved in mitochondrial iron homeostasis, regulation of oxidative phosphorylation, and protection against oxidative stress. CISD1 is also implicated in lipid metabolism and insulin sensitivity. Mutations and altered expression have been linked to metabolic disorders and cancer.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Type 2 Diabetes | CISD1 (mitoNEET) modulates mitochondrial iron and reactive oxygen species (ROS) production, affecting insulin sensitivity in adipocytes and muscle. | Evidence: Studies in mouse models and cell lines show that mitoNEET overexpression improves insulin sensitivity, while knockdown impairs it (e.g., PMID: 20018946). |
| Cancer (e.g., breast, liver) | CISD1 is overexpressed in several cancers, promoting cell proliferation and survival by regulating mitochondrial bioenergetics and iron metabolism. | Evidence: COSMIC lists CISD1 mutations in various cancers; functional studies show that knockdown reduces tumor growth in xenograft models (e.g., PMID: 26077611). |
| Neurodegenerative disorders (e.g., Parkinson's disease) | Mitochondrial dysfunction and iron accumulation are hallmarks; CISD1 may influence neuronal survival via ROS regulation. | Evidence: Indirect evidence from mitochondrial iron studies; no direct clinical association yet, but CISD1 is expressed in brain tissues. |
| Obesity and metabolic syndrome | CISD1 regulates lipid accumulation and mitochondrial function in adipose tissue, contributing to metabolic dysregulation. | Evidence: Animal studies show that CISD1 knockout mice have altered lipid metabolism and increased oxidative stress (e.g., PMID: 24930954). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Heart | 12.2 | Medium |
| Liver | 8.5 | Low |
| Skeletal Muscle | 15.3 | Medium |
| Adipose Tissue | 20.1 | High |
| Brain | 6.4 | Low |
| Kidney | 10.0 | Medium |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (liver cancer) | 18.5 | High expression; used in metabolic studies |
| MCF7 (breast cancer) | 22.3 | High expression; associated with proliferation |
| A549 (lung cancer) | 12.0 | Moderate expression |
| SH-SY5Y (neuroblastoma) | 8.2 | Low expression; neuronal model |
| HeLa (cervical cancer) | 15.7 | Moderate-high expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.292C>T (p.Arg98Cys) | Missense | Rare (0.01% in gnomAD) | Alters Fe-S cluster binding, reducing protein stability and function. |
| c.1A>G (p.Met1Val) | Start loss | Very rare | Loss of translation initiation, leading to loss of function. |
| c.214G>A (p.Gly72Ser) | Missense | Not reported in large cohorts | Potential effect on protein folding; functional impact unknown. |
| c.345_346insA (frameshift) | Insertion | Somatic in cancer (COSMIC) | Predicted to cause truncation and loss of function. |
Mutation functional classification
Loss of Function (LOF)
Mutations that disrupt the iron-sulfur cluster coordination (e.g., Cys residues) or cause premature truncation lead to loss of mitoNEET function, impairing mitochondrial iron regulation and increasing oxidative stress.
Gain of Function (GOF)
No clear gain-of-function mutations have been reported; overexpression of wild-type CISD1 is observed in cancers, suggesting a potential oncogenic role via increased mitochondrial activity.
Dominant Negative (DN)
No evidence for dominant-negative effects; CISD1 functions as a homodimer, but mutations that affect dimerization could theoretically exert dominant-negative effects, though not documented.
View complete mutation data：
Gene Ontology (GO)
| • Iron-sulfur cluster binding (GO:0051536) | • 2 sulfur cluster binding (GO:0051537) |
| • Metal ion binding (GO:0046872) | • Mitochondrial outer membrane (GO:0005741) |
| • Integral component of membrane (GO:0016021) | • Regulation of mitochondrial membrane potential (GO:0051881) |
| • Cellular response to oxidative stress (GO:0034599) | • Iron ion homeostasis (GO:0055072) |
Pathways
• Mitochondrial iron-sulfur cluster biogenesis
• Reactive oxygen species (ROS) metabolism
• Insulin signaling pathway (via regulation of mitochondrial function)
• Apoptosis regulation (via mitochondrial permeability)
Protein Summary
MitoNEET (CISD1) is a 108-amino acid protein localized to the mitochondrial outer membrane, with a cytosolic C-terminal domain containing a CDGSH-type [2Fe-2S] cluster. It forms a homodimer and is involved in iron homeostasis, mitochondrial electron transport, and regulation of oxidative stress. The protein is highly expressed in adipose tissue and skeletal muscle, and its expression is modulated in metabolic and neoplastic conditions. CISD1 has been studied as a drug target for diabetes and cancer, with small molecules like pioglitazone binding to it.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CISD1 Knockout HEK293 Cell Line | EDJ-KQ3719 | Human | 55847 | Details Get a Quote |
| CISD1 Knockout A-549 Cell Line | EDJ-KQ18271 | Human | 55847 | Details Get a Quote |
| CISD1 Knockout HeLa Cell Line | EDJ-KQ24388 | Human | 55847 | Details Get a Quote |
| CISD1 Knockout HCT 116 Cell Line | EDJ-KQ25755 | Human | 55847 | Details Get a Quote |
