aco2-protein

Migration, Crosslink

📖

aco2-protein

active

wiki page Created: 2026-04-02T07:19:10 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-proteins-aco2-protein

📖 Wiki Page

protein1242 wordssynced 2026-04-02

ACO2 Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">aco2-protein</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[ACO2](/genes/aco2)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>[Q99798](https://www.uniprot.org/uniprot/Q99798)</td>
</tr>
<tr>
<td class="label">PDB</td>
<td>5O8T, 6G19, 7B2Y</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~82 kDa</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Mitochondrial matrix</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Iron-sulfur isomerase (Aconitase) family</td>
</tr>
<tr>
<td class="label">Chain Length</td>
<td>780 amino acids</td>
</tr>
<tr>
<td class="label">Metal Cofactor</td>
<td>4Fe-4S cluster</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/parkinson" style="color:#ef9a9a">Parkinson</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">29 edges</a></td>
</tr>
</table>

Overview

...

ACO2 Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">aco2-protein</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[ACO2](/genes/aco2)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>[Q99798](https://www.uniprot.org/uniprot/Q99798)</td>
</tr>
<tr>
<td class="label">PDB</td>
<td>5O8T, 6G19, 7B2Y</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~82 kDa</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Mitochondrial matrix</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Iron-sulfur isomerase (Aconitase) family</td>
</tr>
<tr>
<td class="label">Chain Length</td>
<td>780 amino acids</td>
</tr>
<tr>
<td class="label">Metal Cofactor</td>
<td>4Fe-4S cluster</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/parkinson" style="color:#ef9a9a">Parkinson</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">29 edges</a></td>
</tr>
</table>

Overview

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
Provides intermediates for amino acid synthesis
Generates reducing equivalents (NADPH)
Supports heme biosynthesis

Iron-Sulfur Cluster Biogenesis

ACO2 requires proper iron-sulfur cluster assembly:

ISC machinery: Iron-sulfur cluster (ISC) pathway in mitochondria
Frataxin: Essential cofactor for ISC assembly (Friedreich's ataxia gene)
Assembly factors: ISCU, ISCA, NFS1, ferredoxin

Role in Neurodegeneration

Alzheimer's Disease

Mitochondrial dysfunction is an early hallmark of AD[@chen2021]:

Activity Reduction

ACO2 activity is reduced in AD brains and models
Loss correlates with disease severity
Precedes visible pathology in some models

Iron Dysregulation

Iron accumulation in AD brains affects 4Fe-4S cluster integrity
Oxidative stress damages the iron-sulfur cluster
Reduced aconitase activity contributes to energy deficits

TCA Cycle Impairment

Loss of ACO2 function leads to impaired TCA cycle activity
Reduced ATP production in neurons
Compensatory shifts to glycolysis (Warburg effect)

Therapeutic Implications

Iron chelation therapy may protect aconitase
Antioxidants can preserve 4Fe-4S clusters
Mitochondrial-targeted compounds in development

Parkinson's Disease

PD is associated with mitochondrial complex I deficiency[@liu2020]:

Mitochondrial Vulnerability

Dopaminergic neurons are particularly vulnerable to energy deficits
ACO2 activity reduced in PD substantia nigra
Mutations in ACO2-related genes cause parkinsonism

Iron Homeostasis

Iron accumulation in PD substantia nigra
Disrupted iron homeostasis impacts ACO2 function
Interaction with α-synuclein aggregation

Connections to PINK1/Parkin

Mitochondrial quality control pathways affected
Damaged ACO2 not properly cleared
Autophagy-lysosome system impairment

Other Neurodegenerative Disorders

Friedreich's Ataxia

Frataxin deficiency affects iron-sulfur cluster assembly[@martelli2012]
ACO2 activity reduced due to impaired cluster insertion
Similar mechanism to Aconitase 1 (ACO1) deficiency

Iron Accumulation Disorders

Neurodegeneration with brain iron accumulation (NBIA)
Disrupted iron homeostasis impacts ACO2 function
Common pathway to neuronal death

Huntington's Disease

Mitochondrial dysfunction in HD
ACO2 activity altered in HD models
Energy deficits contribute to progression

Therapeutic Targeting

Current Approaches

Mitochondrial Function Support

Coenzyme Q10: Supports electron transport chain function
Alpha-lipoic acid: Antioxidant that supports mitochondrial function
Creatine: Energy buffer for mitochondrial dysfunction

Iron Homeostasis

Iron chelators: Deferoxamine, deferasirox
Iron regulation: Modulators of ferritin expression

Antioxidant Therapy

Mitochondria-targeted antioxidants: MitoQ, SkQ1
N-acetylcysteine: Precursor to glutathione

Emerging Strategies

Gene Therapy

AAV-mediated ACO2 delivery
Enhanced expression of iron-sulfur cluster assembly factors
Mitochondrial targeting sequences

Small Molecule Activators

Allosteric activators of aconitase
Stabilizers of the 4Fe-4S cluster
Compounds protecting against oxidative damage

Metabolic Modulation

Ketogenic diet for alternative energy sources
Pyruvate supplementation
Dichloroacetate for PDH activation

Key Publications

[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 (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.gov/25916380/)

Cross-Links

[ACO2 Gene](/genes/aco2)
[Mitochondrial Dysfunction in AD](/mechanisms/mitochondrial-dysfunction-alzheimers)
[Iron-Sulfur Cluster Biogenesis](/mechanisms/iron-sulfur-cluster-biogenesis)
[TCA Cycle](/mechanisms/tricarboxylic-acid-cycle)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Iron Metabolism](/mechanisms/iron-metabolism-neurodegeneration)

References

[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/)

External Links

[UniProt: Q99798](https://www.uniprot.org/uniprot/Q99798)
[PDB structures](https://www.rcsb.org/search?q=uniprot:Q99798)
[GeneCards: ACO2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ACO2)

📖 View canonical wiki page →

Related Entities

ACO2PROTEIN

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-aco2-protein
kg_node_id	ACO2PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-9bd088b3f9c2
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-aco2-protein'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

0

Incoming

9

Outgoing

10

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

aco2-protein

ACO2 Protein

Overview

ACO2 Protein

Overview

Protein Infobox

Structure

Iron-Sulfur Cluster

Domain Organization

Conformational Changes

Comparison with Cytosolic ACO1

Normal Function

Catalytic Activity

TCA Cycle Integration

Cellular Metabolism

Iron-Sulfur Cluster Biogenesis

Role in Neurodegeneration

Alzheimer's Disease

Activity Reduction

Iron Dysregulation

TCA Cycle Impairment

Therapeutic Implications

Parkinson's Disease

Mitochondrial Vulnerability

Iron Homeostasis

Connections to PINK1/Parkin

Other Neurodegenerative Disorders

Friedreich's Ataxia

Iron Accumulation Disorders

Huntington's Disease

Therapeutic Targeting

Current Approaches

Mitochondrial Function Support

Iron Homeostasis

Antioxidant Therapy

Emerging Strategies

Gene Therapy

Small Molecule Activators

Metabolic Modulation

Key Publications

Cross-Links

References

See Also

External Links

💬 Discussion