Mitochondrial glutathione peroxidase 4 is indispensable for photoreceptor development and survival in mice.

Glutathione peroxidase 4 (GPx4) is known for its unique function in the direct detoxification of lipid peroxides in the cell membrane and as a key regulator of ferroptosis, a form of lipid peroxidation-induced nonapoptotic cell death. However, the cytosolic isoform of GPx4 is considered to play a major role in inhibiting ferroptosis in somatic cells, whereas the roles of the mitochondrial isoform of GPx4 (mGPx4) in cell survival are not yet clear. In the present study, we found that mGPx4 KO mice exhibit a cone-rod dystrophy-like phenotype in which loss of cone photoreceptors precedes loss of rod photoreceptors. Specifically, in mGPx4 KO mice, cone photoreceptors disappeared prior to their maturation, whereas rod photoreceptors persisted through maturation but gradually degenerated afterward. Mechanistically, we demonstrated that vitamin E supplementation significantly ameliorated photoreceptor loss in these mice. Furthermore, LC-MS showed a significant increase in peroxidized phosphatidylethanolamine esterified with docosahexaenoic acid in the retina of mGPx4 KO mice. We also observed shrunken and uniformly condensed nuclei as well as caspase-3 activation in mGPx4 KO photoreceptors, suggesting that apoptosis was prevalent. Taken together, our findings indicate that mGPx4 is essential for the maturation of cone photoreceptors but not for the maturation of rod photoreceptors, although it is still critical for the survival of rod photoreceptors after maturation. In conclusion, we reveal novel functions of mGPx4 in supporting development and survival of photoreceptors in vivo.

Effect of Lecithin-Bound Iodine Treatment on Inherited Retinal Degeneration in Mice.

Purpose: Although lecithin-bound iodine (LBI) has been administered orally for retinal diseases, a lack of clinical studies and obscure action mechanism of LBI hinder its large-scale prescription. LBI treatment suppresses chemokine (C-C motif) ligand 2 (CCL2) secretion from retinal pigment epithelial cells in vitro. Herein, we assessed the in vivo effect of LBI treatment on retinal degeneration (RD) in mice. Methods: Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice-a model for RD-demonstrate fluorescein-labeled microglia/macrophage to facilitate visualization of CX3CR1-green fluorescent protein (GFP) and CCR2-red fluorescent protein (RFP). An LBI-containing mouse diet was provided to Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice ad libitum from postnatal day (POD) 28. CX3CR1-GFP and CCR2-RFP expression was assessed at POD 56 using retinal sectioning and flat mounting. RD severity was assessed at POD 84. Retinal RNA was extracted from the mice of each group to measure chemokine expression. Electroretinography was performed to assess retinal function. Results: CCR2-RFP expression in the retina and retinal pigment epithelial cells was suppressed by LBI treatment compared with that in the control at POD 56. The number of outer nuclear layer nuclei was higher in the group fed with LBI-containing diet than in the control mice at POD 84. Ccl2 and Ccr2 RNA expression was suppressed by LBI intake. Electroretinography showed the LBI-treated group to have a high b-wave amplitude compared with the control group. Conclusions: Suppressing CCR2-RFP-positive macrophage invasion into the retina and CCL2 and CCR2 expression is a potential mechanism underlying LBI-mediated attenuation of RD. Translational Relevance: Life-long LBI administration may become a candidate for treating RD.