June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Conditional knockout of hephaestin in the neural retina disrupts retinal iron homeostasis
Author Affiliations & Notes
  • Kevin R Zhang
    Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Bailey Baumann
    Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Ying Song
    Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Jacob Sterling
    Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Samyuktha Guttha
    Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Zbynek Kozmik
    Institute of Molecular Genetics, Akademie ved Ceske republiky, Praha, Czechia
  • Joshua L Dunaief
    Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Kevin Zhang None; Bailey Baumann None; Ying Song None; Jacob Sterling None; Samyuktha Guttha None; Zbynek Kozmik None; Joshua Dunaief None
  • Footnotes
    Support  GACR 21-27364S, EY105240, EY007035, Research to Prevent Blindness, the Paul and Evanina Bell Mackall Foundation Trust
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2485 – F0192. doi:
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    • Get Citation

      Kevin R Zhang, Bailey Baumann, Ying Song, Jacob Sterling, Samyuktha Guttha, Zbynek Kozmik, Joshua L Dunaief; Conditional knockout of hephaestin in the neural retina disrupts retinal iron homeostasis. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2485 – F0192.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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