The Labile Side of Iron in Health and Disease: A Narrative Review

Labile iron is an exchangeable and redox-active form of Fe²⁺/Fe³⁺ that is identified in cells under normal or pathological conditions, particularly with the aid of an increasing number of metal-sensitive probes, especially those carrying fluorescent-based sensors, some targetable to specific cell organelles, some useful for real-time measurements. Cell labile iron pools (LIPs) are associated with multiple ligands, predominantly as Fe²⁺-GSH adducts, whose chemical identity remains to be firmly identified. Estimated cellular LIP levels are in the lower μMolar range, rising substantially in systemic iron overload, thus serving as targets for screening of drugs for chelation efficacy and protection from oxidative damage, including ferroptosis. Pathological LIP elevation in specific organs and/or cells results from mutations that affect some FeS-cluster (ISC) protein biogenesis, as in Wolfram syndrome-2 (WS2) patients, who lack NAF-1 (a member of the CISD-coded NEET protein family that carries labile ISCs). In cells from WS2 patients or shRNA NAF-1-repressed, there are elevated mitochondrial LIP and ROS together with reduced GSH levels that are accompanied by morphological and functional damage, most significantly correctable by applying anti-ferroptotic measures, including a conservative form of chelation in conjunction with an antioxidant, offering novel opportunities to treat the otherwise incurable WS2.