| Aconitase 1 (ACO1), also known as cytosolic aconitase or iron regulatory protein 1 (IRP1), is a bifunctional member of the aconitase family that links intermediary metabolism with iron homeostasis by switching between an enzymatic aconitase state and an RNA‑binding regulatory state depending on the status of its iron–sulfur cluster. The protein contains a [4Fe–4S] cluster embedded in a multi‑domain scaffold that positions one iron atom in a solvent‑exposed pocket, allowing direct interaction of the cluster with citrate and cis‑aconitate during catalysis and creating the structural basis for its sensitivity to iron availability and oxidative modifications. In its holo form carrying an intact [4Fe–4S] cluster, ACO1 catalyzes the reversible isomerization of citrate to isocitrate via cis‑aconitate, integrating into the cytosolic extension of the tricarboxylic acid cycle and influencing citrate–isocitrate flux that supports NADPH generation and acetyl‑CoA supply for biosynthetic pathways. Loss or disassembly of the iron–sulfur cluster converts ACO1 into an apo form that undergoes conformational rearrangement to expose RNA‑binding surfaces, enabling high‑affinity recognition of iron‑responsive elements (IREs) in the untranslated regions of mRNAs encoding ferritin, transferrin receptor and other iron‑handling proteins. Binding of IRP1/ACO1 to IREs in ferritin mRNA represses its translation, while interaction with IREs in transferrin receptor mRNA stabilizes the transcript and supports continued receptor synthesis, establishing a post‑transcriptional regulatory circuit that adjusts iron storage and uptake according to intracellular iron levels. Changes in iron availability and in Fe–S cluster biogenesis alter the balance between the aconitase and IRE‑binding states, so that iron sufficiency favors the catalytic aconitase conformation and directs citrate flux, whereas iron depletion or disruption of Fe–S assembly promotes the RNA‑binding form and enhances control over iron transport and storage gene expression. Reactive oxygen and nitrogen species, including superoxide and hydrogen peroxide, oxidize the Fe–S cluster and trigger its disassembly, which reduces aconitase catalytic activity and increases IRP1‑type regulatory behavior, indicating that ACO1 also functions as a sensor of redox and inflammatory conditions that intersect with iron metabolism. In adipose tissue, modulation of ACO1 expression and activity affects adipogenic capacity by altering isocitrate dehydrogenase expression, NADPH/NADP ratios and transferrin receptor levels, tying its metabolic and iron‑regulatory actions to the maintenance of adipose energy metabolism and iron uptake. At the pathway level, ACO1 occupies a nodal position between the citric acid cycle, iron transport and storage systems, and oxidative stress responses, and its structural capacity to undergo an Fe–S‑dependent conformational transition provides a mechanistic framework for studying how cells coordinate ATP production, biosynthetic demand and iron handling in physiological and disease contexts. |
