Figure 5. Redox switching of the labile iron pool (LIP) influences the activity of Jumonji C domain containing histone demethylases (JmjC) and Ten-eleven translocation methylcytosine dioxygenases (TET).

The reactions between reactive oxygen species and iron influences the cellular functions in multiple cellular compartments to influence development. In the mitochondria, aberrant reduction of oxygen can create superoxide (O₂^•−) that disrupts iron sulfur clusters (Fe/S) and heme biosynthesis. In the cytosol, Fe²⁺ exists as free iron in a LIP where it can be assimilated into the catalytic core of enzymes. Fe³⁺ availability is tightly regulated by iron binding proteins such as ferritin that can transport iron into the nucleus. TETs and JmjCs require and Fe²⁺, O₂, and α-ketoglutarate (αKG) during the oxidation of 5-methylcytosine (5mc) in DNA and demethylation of methylated lysines (meK) within histone tails. Spurious events during the respective mechanisms of these enzymes can result in incorrect reduction of iron to its Fe³⁺ state, rendering them inactive (orange pentagon). To regain their activity, these enzymes likely release Fe³⁺ where it is readily reduced by ascorbate (Asc⁻) to create Fe²⁺ and ascorbate radical (Asc^•−). Fe²⁺can then either be reintroduced into enzymes or remain within the nuclear LIP where it can react with ROS originating from enzymes such as NAD(P)H oxidase 4 (NOX4). These redox reactions can then decrease Fe²⁺availblity to JmjC and TET enzymes. Free radical and ROS scavenging systems such as superoxide dismutases 1 and 3 (SOD1/3), glutathione peroxidases (GPx), peroxiredoxins (Prx) work to counter these reactions from happening. Thus, modulating the redox status of iron is one means by which the activity of TET and JmjC enzymes can be controlled.