ACO2 (Aconitase 2, mitochondrial) is an iron-sulfur cluster-containing enzyme that catalyzes the reversible isomerization of citrate to isocitrate in the citric acid (TCA) cycle[@lill1999]. Located in the mitochondrial matrix, ACO2 plays a critical role in cellular energy metabolism through oxidative phosphorylation. The enzyme requires an iron-sulfur [4Fe-4S] cluster for its catalytic activity, making it sensitive to oxidative stress and iron homeostasis disruptions implicated in neurodegenerative diseases.
ACO2 is encoded by the ACO2 gene and is essential for normal mitochondrial function. The enzyme is distinct from the cytosolic aconitase (ACO1), which functions in iron regulatory protein (IRP) post-transcriptional regulation. Mitochondrial ACO2 activity is reduced in several neurodegenerative conditions, including [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease)[@wang2020].
Protein Infobox
Structure
ACO2 is a 780-amino acid protein with a complex structure enabling its catalytic function[@giachin2016]:
Iron-Sulfur Cluster
The active site contains a [4Fe-4S] iron-sulfur cluster essential for catalysis:
Cluster composition: Four iron atoms coordinated by four inorganic sulfides
Cysteine ligands: Cys358, Cys360, Cys365, and Cys391 coordinate the cluster
Catalytic role: The cluster acts as a Lewis acid, facilitating citrate isomerization
Sensitivity: The cluster is highly sensitive to oxidative stress and nitric oxide
Domain Organization
N-terminal domain: Contains the active site with the 4Fe-4S cluster
C-terminal domain: Forms a beta-barrel structure supporting the active site
Alpha-helical insertion: Regulatory region between domains
Conformational Changes
Substrate binding induces conformational changes
The enzyme undergoes "open" and "closed" states during catalysis
Post-translational modifications can modulate activity
Comparison with Cytosolic ACO1
ACO2 (mitochondrial): Purely enzymatic function in TCA cycle
ACO1 (cytosolic): Dual function - enzymatic and iron regulatory
Sequence similarity: ~60% identical at amino acid level
Normal Function
In the mitochondria, ACO2 catalyzes the second step of the TCA cycle[@wang2020]:
Catalytic Activity
Reaction: Citrate ⇌ Isocitrate
Mechanism: Through a dehydration/hydration mechanism
Intermediate: Formed as cis-aconitate (bound to enzyme)
Rate: High turnover number under physiological conditions
TCA Cycle Integration
ACO2 is essential for normal TCA cycle function:
Step 2: Citrate (6C) → Isocitrate (6C)
Step 3: Isocitrate → α-Ketoglutarate + CO2 (IDH catalyzed)
Energy production: Generates NADH for oxidative phosphorylation
Anaplerosis: Provides carbon skeletons for biosynthesis
Cellular Metabolism
Supports oxidative phosphorylation and ATP production
[Lill R, et al, The iron-sulfur cluster proteins aconitase and iron regulatory protein 1 (1999)](https://pubmed.ncbi.nlm.nih.gov/10924579/)
[Giachin G, et al, Structure of human mitochondrial aconitase (2016)](https://pubmed.ncbi.nlm.nih.gov/26931675/)
[Wang T, et al, Mitochondrial dysfunction and therapeutic targets in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32871064/)
[Keeney PM, et al, Alzheimer's disease brain mitochondrial dysfunction and melancholia (2013)](https://pubmed.ncbi.nlm.nih.gov/23687164/)
[Martelli A, et al, Iron metabolism and mitochondrial disorders (2012)](https://pubmed.ncbi.nlm.nih.gov/22460445/)
[Rouault TA, et al, Mitochondrial iron metabolism and disease (2012)](https://pubmed.ncbi.nlm.nih.gov/22674208/)
[Chen X, et al, Mitochondrial dysfunction in Alzheimer's disease: molecular mechanisms and therapeutic strategies (2021)](https://pubmed.ncbi.nlm.nih.gov/34023426/)
[Liu Y, et al, Aconitase activity and expression in Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/31785019/)
[Crofts AR, et al, Cytochrome bc1 complex and mitochondrial iron homeostasis (2013)](https://pubmed.ncbi.nlm.nih.gov/23220359/)
[Fenton WA, et al, Iron-sulfur cluster biogenesis and human disease (2015)](https://pubmed.ncbi.nlm.nih.com/25916380/)
See Also
[ACO2 Gene](/genes/aco2)
[Mitochondrial dysfunction in AD](/entities/mitochondria)
[Iron-sulfur cluster biogenesis](/content/genes)
[TCA Cycle](/mechanisms/tricarboxylic-acid-cycle)
[Iron Metabolism in Neurodegeneration](/mechanisms/iron-metabolism-neurodegeneration)