| Aconitase 2 (ACO2) is the mitochondrial isoform of the aconitase/IPM isomerase family that catalyzes the reversible isomerization of citrate to isocitrate via cis‑aconitate in the tricarboxylic acid cycle and functions as a [4Fe–4S] iron–sulfur dehydratase whose activity is tightly coupled to both oxidative metabolism and mitochondrial iron homeostasis. The enzyme is encoded in the nucleus, imported into the mitochondrial matrix and organized into four domains with an α/β‑alternating fold that buries a single active site in the core of the protein; three cysteine residues coordinate a [4Fe–4S] cluster that does not participate in electron transfer but instead orients and activates the substrate hydroxyl group for elimination and readdition, with citrate or isocitrate binding at this cluster and conserved residues such as His101, His167, Asp100, Glu262 and Ser642 orchestrating proton transfer and intermediate formation during the two‑step dehydratase/rehydratase mechanism. The iron–sulfur cluster is highly sensitive to oxidation by reactive oxygen and nitrogen species, and exposure to mitochondrial ROS causes loss of iron from the cluster, conversion to an inactive [3Fe–4S] state and degradation of oxidatively modified ACO2 by the Lon protease PRSS15, so that ACO2 acts as both a metabolic enzyme and a redox‑sensitive node linking oxidative stress to TCA cycle flux and mitochondrial protein turnover. Reviews of mitochondrial aconitase emphasize that ACO2 is one of the main targets of mitochondrial ROS/RNS and plays important roles in maintaining the intracellular iron pool and mitochondrial DNA stability, with inactivation or dysfunction of ACO2 leading to altered bioenergetics, disturbed iron homeostasis and increased susceptibility to neurodegenerative diseases such as Friedreich’s ataxia, Parkinson’s disease and Alzheimer’s disease, in which decreased Fe‑S protein activity and mitochondrial iron accumulation are common features. In Friedreich’s ataxia, frataxin mutation is associated with deficiency of Fe‑S cluster–containing respiratory complexes I–III and aconitase in cardiac tissue and yeast models, supporting a mechanism in which mitochondrial iron overload and oxidative damage compromise ACO2 activity and contribute to cardiomyopathy and neurodegeneration, and similar Fe‑S vulnerability is seen in other mitochondrial disorders. Cancer studies show that ACO2 participates in metabolic rewiring: ACO2 expression is reduced in several tumors, and forced ACO2 overexpression in MCF‑7 breast cancer cells impairs proliferation, redirects pyruvate toward mitochondrial oxidation, weakens Warburg‑like glycolytic features and promotes ROS‑dependent FoxO1‑mediated autophagy and mitophagy, indicating that ACO2 levels influence the balance between glycolytic and oxidative metabolism and can reveal metabolic vulnerabilities in ACO2‑associated malignancies. Genetic inhibition of mitochondrial aconitase in C. elegans and mammalian cells lowers oxaloacetate levels, enhances the mitochondrial unfolded protein response via ATFS‑1 and increases immunity against pathogenic bacteria, showing that ACO2‑dependent metabolism suppresses innate immune activation and that targeting ACO2 can modulate mitochondrial UPR and host defense. |
