Stability And Functionality Of Hl Heteropolymer Ferritins Responsible For A Hereditary Ferritinopathy Disorder

Mammalian ferritins typically consist of 24 structurally similar but functionally different subunit types named H and L capable of accommodating up to 4500 Fe atoms per molecule. Heteropolymer ferritins having mutations on the L-subunit cause hereditary ferritinopathy, a neurodegenerative disease characterized by abnormal accumulation of ferritin and iron in the central nervous system. Here, we characterize three pathogenic L-ferritin mutants (L154fs, L167fs, and L148fs also known as Ln1, Ln2 and L442P) and one non-pathogenic variant (L135P) for their iron uptake, oxidation and release properties. Overall, the data show iron loading capacity ranging between 1800–2400 Fe/shell for all HL samples with Ln2 holding the least amount of iron. The order of stability of the HL samples is HL > H-chain > L135P > Ln2 > Ln1 > L442P. The rates of Fe oxidation were similar in all HL samples with a consistently noticeable higher rate with L442P. The mechanism of Fe oxidation appeared to proceed mainly via a ferroxidation reaction with about ~ 2:1 Fe:O2 ratio and slowly climbing to ~ 3:1 at higher iron loadings. Ln1 and L442P had a higher rate of Fe mobilization consistent with the onset of neuroferritinopathy. This work is supported by a Kilmer Apprenticeship and a Cottrell College Science Award (ID # 7892) from Research Corporation.