| Ferritin light chain (FTL) constitutes the light subunit of the 24-mer ferritin nanocage responsible for intracellular iron storage in a soluble, non-toxic, and bioavailable form, thus buffering labile Fe²⁺ and supporting iron homeostasis while protecting cells from iron-induced oxidative damage. The ferritin complex is built from heavy (H) and light (L) chains, forming a hollow spherical shell; H subunits possess ferroxidase centers that convert Fe²⁺ to Fe³⁺, whereas L subunits create an interior carboxylate-rich environment that supports nucleation, mineralization, and stabilization of the ferric oxyhydroxide mineral core. While FTL lacks intrinsic ferroxidase activity, ferritins with higher L-chain content promote efficient mineral core formation and modulate rates of iron uptake and release, with the H:L ratio in the 24-mer determining the kinetics of iron oxidation, storage, and mobilization across tissues. Iron mobilization from ferritin occurs through lysosomal degradation of the protein shell in a process termed ferritinophagy, mediated by the cargo receptor NCOA4, which selectively binds ferritin, directs H/L heteropolymers to autophagosomes, and targets them to lysosomes, where proteolysis releases Fe²⁺ for cellular metabolism or, when dysregulated, contributes to iron-dependent cell death mechanisms such as ferroptosis. Expression of FTL and FTH1 is tightly regulated at the translational level via iron-responsive elements in their 5′UTRs that bind iron-regulatory proteins, and by additional post-transcriptional mechanisms, including direct translational repression of FTL mRNA by eIF3 through specific 5′UTR binding, ensuring integration of systemic and cellular iron status with ferritin light chain synthesis. Germline mutations disrupting the FTL IRE cause hereditary hyperferritinemia-cataract syndrome, characterized by constitutive L-ferritin overproduction, elevated serum ferritin without iron overload, and early-onset cataracts, demonstrating that dysregulation of FTL is sufficient to alter systemic ferritin and cause tissue pathology. |
