Iron–Sulfur Cluster Metabolism Impacts Iron Homeostasis, Ferroptosis Sensitivity, and Human Disease

Iron is the most abundant transition metal in biological systems owing in part to its participation in O2 transport and electron transfer reactions. We describe how, in mammals, the redox-active nature of iron is managed at the cellular level, particularly regulation by iron-response proteins (IRPs), and discuss how intracellular iron regulates IRPs. We define the role of iron in promoting oxidative cell death, termed ferroptosis, when these homeostatic iron regulatory mechanisms are perturbed, and review the evidence for cellular iron levels modulating ferroptosis sensitivity. We focus particularly on the role of iron in the iron–sulfur cluster (ISC), a protein cofactor that serves numerous roles in the cell, including a key role as an iron sensor. We illustrate that ISC biosynthesis inhibition causes aberrant activation of IRPs and an iron-overloaded state that sensitizes cells to ferroptosis. We provide evidence that lung adenocarcinomas select for the key ISC biosynthetic enzyme, NFS1, to shield themselves from the damaging effects of O2 on ISCs and protect from iron-catalyzed oxidative stress. Finally, we ask whether dysregulation of ISC synthesis, observed in multiple pathological settings including neurodegenerative diseases such as Friedreich’s Ataxia, sideroblastic anemia, and cancer, leads to pathology as a result of ferroptosis.