ACO2 encodes aconitase 2, a mitochondrial enzyme that catalyzes the isomerization of citrate to isocitrate via cis-aconitate in the tricarboxylic acid (TCA) cycle 1. The enzyme contains a 4-iron-4-sulfur cluster essential for its catalytic activity and functions primarily in the mitochondrial matrix, though nuclear localization has also been identified as part of a nonclassical nuclear TCA cycle 1. ACO2 plays a crucial role in cellular energy metabolism by facilitating the second step of the TCA cycle, generating metabolic intermediates necessary for ATP production and biosynthetic pathways 2. Pathogenic variants in ACO2 cause dominant and recessive forms of optic atrophy, with biallelic mutations associated with more severe phenotypes including infantile cerebellar-retinal degeneration 3. ACO2 represents the third most frequently mutated gene in autosomal inherited optic neuropathies after OPA1 and WFS1 3. Patient fibroblasts with ACO2 mutations show reduced enzyme abundance and activity, impaired mitochondrial respiration with citrate/pyruvate substrates, and decreased mitochondrial DNA content 3. The protein also serves as a therapeutic target, as α-synuclein binding to ACO2 contributes to mitochondrial dysfunction in Parkinson's disease models 4.