Citrate's Role as the Fulcrum in Iron Regulation and Homeostasis

The multifunctional, iron-sulfur cluster-dependent enzyme aconitase catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid cycle. Its cytosolic isoform, aconitase 1, also functions as iron regulatory protein 1 under iron-deficient conditions to regulate cellular iron levels. The iron-transport protein transferrin (TF) delivers iron into cells via the endocytic pathway and consists of two lobes—the N-lobe and C-lobe—that bind iron with distinct affinities and signaling outcomes. Using the MIDAS platform we discovered a novel protein-interaction between citrate and transferrin, illuminating a bridge between the two fundamental biological systems. Our preliminary data shows that citrate binds to transferrin in a pH dependent mechanism. We are currently trying to understand where and how citrate binds and its larger role in iron homeostasis.

Our current hypothesis is that citrate is fundamental to the regulation of iron released from transferrin along with its shown regulation of iron protein transcription playing the fulcrum in balancing two biological processes.