| ACO2 | |
|---|---|
| Full Name | Aconitase 2 |
| Location | Chr 22q13.2 |
| NCBI Gene ID | 50 |
| OMIM | 100850 |
| Ensembl | ENSG00000100412 |
| UniProt | Q99798 |
| Associated Diseases | Infantile cerebellar-retinal degeneration, Neurodegeneration, Cancer |
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[1]. 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[2].
The ACO2 gene is located on chromosome 22q13.2 and spans approximately 42 kb with 18 exons. Key features include:
The mature protein (778 amino acids) forms a homodimer and contains a cubane 4Fe-4S cluster essential for catalysis[3].
ACO2 catalyzes the second step of the TCA cycle:
ACO2 serves as a sensitive redox sensor due to its iron-sulfur cluster:
ACO2 is linked to cellular iron homeostasis:
ACO2 activity integrates with:
Biallelic ACO2 mutations cause a severe autosomal recessive disorder:
ACO2 dysfunction contributes to common neurodegenerative conditions:
Friedreich's Ataxia:
ACO2 shows altered expression in several cancers:
ACO2 is ubiquitously expressed in all nucleated cells:
The Allen Brain Atlas shows enriched ACO2 expression in cerebellar Purkinje cells and cortical pyramidal neurons[11].
| Variant | rsID | Effect | Significance |
|---|---|---|---|
| rs2363740 | Intronic | Gene expression | eQTL |
| rs729388 | 3' UTR | mRNA stability | Uncertain |
Potential approaches to support ACO2 function:
ACO2 protection may benefit from:
Beinert H, Kennedy MC, Stout CD. Aconitase as iron-sulfur protein, enzyme, and iron-regulatory protein. Chemical Reviews. 1996. ↩︎
Gardner PR. Aconitase: sensitive target and measure of superoxide. Methods in Enzymology. 2002. ↩︎
Lauble H, Kennedy MC, Beinert H, Stout CD. Crystal structures of aconitase with isocitrate and nitroisocitrate bound. Biochemistry. 1992. ↩︎
Krebs HA. The citric acid cycle and the Szent-Györgyi cycle in pigeon breast muscle. Biochemical Journal. 1940. ↩︎
Yan LJ, Levine RL, Sohal RS. Oxidative damage during aging targets mitochondrial aconitase. Proceedings of the National Academy of Sciences. 1997. ↩︎
Gentile F, et al. Metabolic reprogramming in neurodegenerative diseases. Journal of Neuroscience Research. 2021. ↩︎
Metodiev MD, et al. Mutations in the mitochondrial aconitase gene ACO2 cause infantile cerebellar-retinal degeneration. Journal of Medical Genetics. 2014. ↩︎
Gibson GE, et al. Deficits in the mitochondrial enzyme aconitase in Alzheimer's disease brain. Neurobiology of Aging. 2000. ↩︎
Schapira AH. Mitochondrial dysfunction in Parkinson's disease. Journal of Neurology. 2009. ↩︎
Ristoff E, et al. Iron-sulfur cluster deficiency in Friedreich's ataxia. Journal of Neurochemistry. 2019. ↩︎
Hawrylycz MJ, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012. ↩︎
Botta A, et al. Therapeutic strategies for mitochondrial aconitase deficiency. Molecular Genetics and Metabolism. 2020. ↩︎