The Iron Maiden. Cytosolic Aconitase/IRP1 Conformational Transition in the Regulation of Ferritin Translation and Iron Hemostasis

Abstract

Maintaining iron homeostasis is fundamental for almost all living beings, and its deregulation correlates with severe and debilitating pathologies. The process is made more complicated by the omnipresence of iron and by its role as a fundamental component of a number of crucial metallo proteins. The response to modifications in the amount of the free-iron pool is performed via the inhibition of ferritin translation by sequestering consensus messenger RNA (mRNA) sequences. In turn, this is regulated by the iron-sensitive conformational equilibrium between cytosolic aconitase and IRP1, mediated by the presence of an iron–sulfur cluster. In this contribution, we analyze by full-atom molecular dynamics simulation, the factors leading to both the interaction with mRNA and the conformational transition. Furthermore, the role of the iron–sulfur cluster in driving the conformational transition is assessed by obtaining the related free energy profile via enhanced sampling molecular dynamics simulations.

Spotlight on iron and ferroptosis: research progress in diabetic retinopathy

“…Moreover, the synthesis of isocitrate weaves its narrative dependent upon cis-aconitase, a custodian of iron-sulfur clusters, its essential entity poised at the epicenter of activity. Notably, the synthesis of cis-aconitase pivots upon dynamic transformations ( 17 , 49 ). As a concurrent participant within this tapestry, cis-aconitase is a member of the iron regulatory protein family, oftentimes referred to as IRP-1 ( 28 ).…”

“…As a concurrent participant within this tapestry, cis-aconitase is a member of the iron regulatory protein family, oftentimes referred to as IRP-1 ( 28 ). It operates within a nuanced realm: a deficit in intracellular iron prompts oxidative degradation of IRP-1’s iron-sulfur cluster, resulting in the eclipse of cis-aconitase activity ( 49 ). Thus, the cadence of its activity mirrors the oscillations within intracellular iron homeostasis, assuming its mantle as an important bridge between iron equilibrium and glucose metabolism.…”

Iron Metabolism in Normal and Pathological Conditions

“…Гомеостаз заліза в організмі забезпечується, в першу чергу, регуляцією його всмоктування у шлунково-кишковому тракті (ШКТ) у зв'язку з обмеженою здатністю організму до виділення цього елементу. Існує зворотній зв'язок між забезпеченням організму залізом та його всмоктуванням у травному тракті [2,4,[6][7][8].…”

“…Існуєінший шлях цебезпосереднєвикористанняеритрокаріоцит амиферитиновогозалізаізвласноїклітини і з макрофагів без участітрансферину, але роль цьогомеханізму у фізіологічномуеритропоезі остаточно не вивчена [7,10].…”

A Bioinformatics-Assisted Review on Iron Metabolism and Immune System to Identify Potential Biomarkers of Exercise Stress-Induced Immunosuppression

“…For instance, the FTL/FTH1 complex acts as an Fe storage spherical shell (retaining it when there is too much in the body or releasing it when there is deficiency), while SLC40A1 is the "gateway" of Fe-containing cells (again releasing it or retaining it when necessary) [112,113]. The regulation of these proteins' expression by lymphocytes plays an important role in Fe metabolism via the Fe-sensitive conformational equilibrium between cytosolic aconitase and the IREB/IRE system (which also needs Fe-S clusters) [114]. The FTH/FTL ratio is tissue and context-specific, and dynamically regulated, with FTH becoming more abundant during active inflammation [115].…”