Characterization of Mutant L-Chain Ferritins Responsible for Neuroferritinopathy (2021)

Ferritins are ubiquitous and well-characterized iron storage proteins that play essential roles in cellular iron homeostasis. They consist of 24 structurally similar but functionally different subunit types, named H and L. The two subunits co-assemble in various ratios, with a tissue specific distribution, to form shell-like protein structures of 24 subunits within which a mineralized iron core is stored. Pathogenic mutations on the L-chain lead to neuroferritinopathy, a neurodegenerative disease characterized by abnormal accumulation of ferritin inclusion bodies and iron in the central nervous system. Here, we have characterized three of these pathogenic mutants and found that hereditary neuroferritinopathies are due to structural changes in the ferritin function including lower thermal stability and a mismanagement of iron uptake and release.