Abstract
Purpose :
Intracellular iron can catalyze Fenton chemistry, causing oxidative stress in iron-loaded tissues. The retina is particularly vulnerable to oxidative assault, and iron accumulation has been implicated in retinal degenerative disease. Thus, it is important to understand retinal iron regulation. In mice, systemic knockout of the multi-copper ferroxidases (MCOs), ceruloplasmin (Cp) and hephaestin (Heph), which facilitate cellular iron export, results in retinal iron accumulation and degeneration. However, the role of MCOs within the neural retina is not clear.
Methods :
A neural retina-specific Heph knockout model was generated, using previously developed mRx-Cre and Heph-flox lines, on a background of systemic Cp knockout. qPCR was used to verify Heph KO. Immunohistochemistry for ferritin-L (FtL), ferritin-H (FtH), and transferrin receptor (TfR) were used to determine retinal iron accumulation. Retinal morphology and function were assessed using in vivo retinal photography, optical coherence tomography (OCT), and electroretinography (ERG).
Results :
Conditional KO of Heph in the neural retina in mice with systemic Cp KO resulted in age-dependent neural retina iron accumulation in amacrine cells and photoreceptors. Interestingly, retinal ganglion cells became iron depleted. However, unlike the systemic Cp/Heph double knockout model, there was no retinal degeneration or loss of retinal function.
Conclusions :
MCOs have a local role in regulating neural retina iron homeostasis, with neural retina-specific deletion of MCOs leading to neural retina iron accumulation. Since neural retina-specific KO of Heph does not cause retinal degeneration, such as that observed in systemic double KO mice, preserved Heph function in either the RPE or systemically mitigates the phenotype in the retina-specific Heph KO.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.