ACO2 — Aconitase 2

ACO2 — Aconitase 2

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2">ACO2</th></tr>
<tr><td>Full Name</td><td>Aconitase 2</td></tr>
<tr><td>Location</td><td>Chr 22q13.2</td></tr>
<tr><td>NCBI Gene ID</td><td><a href="https://www.ncbi.nlm.nih.gov/gene/50" target="_blank">50</a></td></tr>
<tr><td>OMIM</td><td><a href="https://www.omim.org/entry/100850" target="_blank">100850</a></td></tr>
<tr><td>Ensembl</td><td><a href="https://www.ensembl.org/Homo_sapiens/Gene/View?g=ENSG00000100412" target="_blank">ENSG00000100412</a></td></tr>
<tr><td>UniProt</td><td><a href="https://www.uniprot.org/uniprot/Q99798" target="_blank">Q99798</a></td></tr>
<tr><td>Associated Diseases</td><td>Infantile cerebellar-retinal degeneration, Neurodegeneration, Cancer</td></tr>
</table>
</div>

Overview

ACO2 — Aconitase 2

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2">ACO2</th></tr>
<tr><td>Full Name</td><td>Aconitase 2</td></tr>
<tr><td>Location</td><td>Chr 22q13.2</td></tr>
<tr><td>NCBI Gene ID</td><td><a href="https://www.ncbi.nlm.nih.gov/gene/50" target="_blank">50</a></td></tr>
<tr><td>OMIM</td><td><a href="https://www.omim.org/entry/100850" target="_blank">100850</a></td></tr>
<tr><td>Ensembl</td><td><a href="https://www.ensembl.org/Homo_sapiens/Gene/View?g=ENSG00000100412" target="_blank">ENSG00000100412</a></td></tr>
<tr><td>UniProt</td><td><a href="https://www.uniprot.org/uniprot/Q99798" target="_blank">Q99798</a></td></tr>
<tr><td>Associated Diseases</td><td>Infantile cerebellar-retinal degeneration, Neurodegeneration, Cancer</td></tr>
</table>
</div>

Overview

[ACO2](/genes/aco2) (Aconitase 2) is a mitochondrial enzyme that catalyzes the stereospecific isomerization of citrate to isocitrate via cis-aconitate in the second step of the tricarboxylic acid (TCA) cycle["@beinert1996"]. Beyond its metabolic role, ACO2 serves as a critical sensor of mitochondrial oxidative stress and iron-sulfur cluster status, linking cellular metabolism to redox homeostasis["@gardner2002"].

Gene and Protein Structure

The ACO2 gene is located on chromosome 22q13.2 and spans approximately 42 kb with 18 exons. Key features include:

• N-terminal mitochondrial targeting sequence: Directs import into mitochondrial matrix
• Four functional domains: Organized around the 4Fe-4S cluster
• 4Fe-4S cluster binding site: Essential for catalytic activity and redox sensing
• Active site: Contains three conserved cysteine residues coordinating the iron-sulfur cluster

Function

TCA Cycle Enzyme

ACO2 catalyzes the second step of the TCA cycle:

• Citrate → cis-Aconitate → Isocitrate: Stereochemical isomerization
• Iron-sulfur cluster catalysis: 4Fe-4S cluster facilitates dehydration/rehydration
• Metabolic flux: Critical control point for energy production[@krebs1940]

Redox Sensor

ACO2 serves as a sensitive redox sensor due to its iron-sulfur cluster:

• Superoxide sensitivity: 4Fe-4S cluster is highly susceptible to oxidation
• Inactivation by [ROS](/entities/reactive-oxygen-species): Superoxide and H₂O₂ inactivate ACO2 by cluster damage
• Redox signaling: ACO2 activity reflects mitochondrial oxidative status[@yan1997]

Iron Metabolism

ACO2 is linked to cellular iron homeostasis:

• Iron-sulfur cluster assembly: Depends on mitochondrial iron availability
• Iron-responsive element binding: Regulated by iron levels (in some species)
• Aconitase/IRP switch: Coordinate regulation of iron metabolism (mainly ACO1 in cytoplasm)

Metabolic Integration

ACO2 activity integrates with:

• [Complex I](/mechanisms/mitochondrial-dysfunction) function through NADH production
• Fatty acid oxidation through acetyl-CoA generation
• Amino acid metabolism through TCA cycle intermediates[@gentile2021]

Disease Associations

Infantile Cerebellar-Retinal Degeneration (ICRD)

Biallelic ACO2 mutations cause a severe autosomal recessive disorder:

• Cerebellar atrophy: Progressive cerebellar degeneration
• Optic atrophy: Retinal degeneration and vision loss
• Developmental delay: Severe neurological impairment
• Hypotonia: Muscle weakness and movement disorders
• Ophthalmoplegia: Eye movement abnormalities[@metodiev2014]

Neurodegenerative Diseases

ACO2 dysfunction contributes to common neurodegenerative conditions:

[Alzheimer's Disease](/diseases/alzheimers-disease):

• Decreased ACO2 activity in AD brains
• Iron-sulfur cluster damage from oxidative stress
• Impaired TCA cycle flux and energy metabolism
• Correlation with disease severity[@gibson2000]

• Reduced ACO2 activity in substantia nigra
• Complex I-ACO2 metabolic coupling impaired
• Oxidative damage to iron-sulfur cluster
• Energy failure in dopaminergic [neurons](/entities/neurons)[@schapira2009]

• Secondary ACO2 deficiency due to iron-sulfur cluster assembly defects
• [FXN](/genes/fxn) mutation impairs ACO2 function
• Metabolic and oxidative stress interplay[@ristoff2019]

Cancer

ACO2 shows altered expression in several cancers:

• Downregulation in some tumor types (Warburg effect)
• Potential tumor suppressor role
• Metabolic reprogramming affects ACO2 expression

Expression

ACO2 is ubiquitously expressed in all nucleated cells:

• Brain: High expression in neurons with high metabolic demand
• Heart: Cardiomyocytes with continuous ATP demand
• Skeletal muscle: Particularly oxidative fibers
• Kidney: Proximal tubules with active metabolism

Common Variants

| Variant | rsID | Effect | Significance |
|---------|------|--------|--------------|
| rs2363740 | Intronic | Gene expression | eQTL |
| rs729388 | 3' UTR | mRNA stability | Uncertain |

Therapeutic Implications

ACO2 Enhancement Strategies

Potential approaches to support ACO2 function:

Antioxidant Interventions

ACO2 protection may benefit from:

• [MitoQ](/therapeutics/mitochondrial-antioxidants): Mitochondrial-targeted antioxidant
• [Coenzyme Q10](/therapeutics/coenzyme-q10-neurodegeneration): Electron carrier and antioxidant
• [N-acetylcysteine](/therapeutics/nacet): Glutathione precursor

See Also

• [ACO1](/genes/aco1) — Cytosolic aconitase (IRP1)
• [IDH2](/genes/idh2) — Isocitrate dehydrogenase 2
• [SDHA](/genes/sdha) — Succinate dehydrogenase
• [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction) — Energy failure in neurodegeneration
• [TCA Cycle](/mechanisms/tca-cycle-dysfunction) — Central metabolic pathway

External Links

• [GeneCards: ACO2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ACO2)
• [UniProt: Q99798](https://www.uniprot.org/uniprot/Q99798)
• [NCBI Gene: 50](https://www.ncbi.nlm.nih.gov/gene/50)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving ACO2 — Aconitase 2 discovered through SciDEX knowledge graph analysis: