A Common Mutation in the Homeostatic Iron Regulatory Gene Alters Astrocyte Migration and Redox Profile

Astrocytes play a vital role in maintaining homeostasis and function in the central nervous system, including their involvement in reparative processes. Here, we examined how a common mutation in the homeostatic iron regulatory gene, H67D HFE, impacts the antioxidant mechanism of astrocytes and migration under normal and reparative conditions. Previous data from our group suggested that this mutation may modify disease progression through an antioxidant mechanism involving nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and ferritin. In this study, we used primary murine astrocytes with either the H67D or wild-type HFE genotype to determine whether astrocytes contribute to the antioxidant protective mechanism previously observed. We analyzed their antioxidant profile and migration both at baseline and after a scratch wound injury. We found that H67D HFE astrocytes expressed the HFE protein and exhibited an enhanced antioxidant profile, marked by increased glutathione and GPX4 at baseline, and a reduced migration length into three-dimensional granular hydrogel scaffolds. However, following scratch wound injury, these astrocytes exhibited a shift in migratory behavior, leading to faster wound infiltration. Moreover, their antioxidant response became even more pronounced after injury, with increased expression of Nrf2, GPX4, and H-ferritin (FTH1). These results suggest that the mechanism underlying HFE mutation neuroprotection in disease processes involves an antioxidant profile in astrocytes, which is increased upon insult to activate the astrocytic reparative mechanism.