ACO1

ACO1 Full Name

aconitase 1, soluble

ACO1 Introduction

Aconitase 1 (ACO1), also known as cytoplasmic aconitase or iron regulatory protein 1 (IRP1), is a multifunctional enzyme that plays dual roles in cellular metabolism and iron homeostasis. As a key component of the tricarboxylic acid (TCA) cycle, ACO1 catalyzes the reversible isomerization of citrate to isocitrate via the intermediate cis-aconitate, a critical step in energy production through aerobic respiration. Beyond its metabolic function, ACO1 acts as an iron regulatory protein (IRP1) when iron levels are low, binding to iron-responsive elements (IREs) in the mRNAs of iron metabolism-related genes to modulate their translation or stability. This dual functionality allows ACO1 to integrate cellular energy metabolism with iron homeostasis, ensuring that iron availability is coordinated with metabolic demands. ACO1 is widely expressed in all mammalian tissues, with high levels in metabolically active organs such as the heart, liver, and skeletal muscle. Today, ACO1 is recognized not only as a core metabolic enzyme but also as a key regulator of iron homeostasis, with profound implications for metabolism, iron-related disorders, and disease pathogenesis.

Figure 1.The structure of ACO1.

Regulation of ACO1/IRP1 Activity and Switching Mechanism
The switch between the enzymatic and RNA-binding states of ACO1 is dynamically regulated by three interconnected mechanisms: iron availability, reactive oxygen/nitrogen species, and post-translational modifications. Under iron‑replete conditions, the assembly of the [4Fe-4S] cluster occurs through the iron‑sulfur cluster biogenesis machinery, including the scaffold protein ISCU and the cysteine desulfurase NFS1. The cluster is inserted into ACO1 with the assistance of chaperones (HSC20, HSPA9) and the glutaredoxin GLRX5, which reduces disulfide bonds to facilitate iron incorporation. Once the cluster is assembled, ACO1 adopts a closed conformation that occludes the RNA-binding surface, favoring aconitase activity. When iron is depleted, the cluster becomes unstable and is degraded — a process that may involve the iron‑sulfur cluster removal protein IBAR (also known as MIP18 or FAM96A), which extracts the iron from the cluster, leaving a [3Fe-4S] intermediate that is ultimately converted to the apoprotein. In the apoprotein form, ACO1 undergoes a conformational rearrangement that exposes a positively charged cleft containing the helix-turn-helix motif responsible for IRE binding. Nitric oxide (NO) and hydrogen peroxide (H2O2) directly damage the [4Fe-4S] cluster by nitrosylating or oxidizing the coordinating iron atoms, causing cluster disassembly and switching ACO1 to the IRP1 state even when iron levels are normal; this pathway explains why inflammation (where NO is produced by iNOS) induces iron retention in macrophages and contributes to the anemia of chronic disease. Phosphorylation of ACO1 at serine 138 and serine 711 by protein kinase C (PKC) and casein kinase 2 (CK2) modulates the rate of cluster assembly and RNA-binding affinity, providing fine-tuning of IRP activity in response to growth factor signaling.

Clinical Significance: ACO1 in Iron Metabolism Disorders and Cancer
Mutations in ACO1 are rare, and only a few families with autosomal recessive ACO1 deficiency have been described. Affected individuals present with a neurological syndrome characterized by cerebellar ataxia, hypotonia, delayed psychomotor development, and elevated serum ferritin levels in the absence of iron overload (hyperferritinemia with normal iron saturation). This paradoxical hyperferritinemia reflects dysregulation of IRP1-mediated ferritin translation: when ACO1 is mutated such that it cannot assemble the [4Fe-4S] cluster, the protein is trapped in the apoprotein state, constitutively binding to the 5' IRE of ferritin mRNA and paradoxically reducing ferritin translation. However, because the hyperferritinemia observed in these patients is not accompanied by iron overload (unlike hereditary hemochromatosis) and does not cause organ damage, the condition is considered benign and termed "hereditary hyperferritinemia without iron overload" due to abnormal IRP1 regulation. More commonly, acquired dysregulation of the ACO1/IRP1 switch is observed in diverse diseases: in sideroblastic anemias, mutations in the iron‑sulfur cluster assembly machinery (e.g., GLRX5, ABCB7) lead to constitutive IRP1 activation, causing ferritin suppression and transferrin receptor upregulation that exacerbates mitochondrial iron accumulation.

Alternate Names for ACO1

ACO1; aconitase 1, soluble; IRP1; ACONS; HEL60; IREB1; IREBP; IREBP1; cytoplasmic aconitate hydratase; IRE-BP 1