Sex-dependent Regulation of Retinal Pigment Epithelium and Retinal Function by

Age-related macular degeneration (AMD) is a major cause of blindness that affects people over 60. While aging is the prominent factor in AMD, studies have reported a higher prevalence of AMD in women compared to age-matched men. Higher levels of the innate immune response's effector proteins complement factor B and factor I were also found in females compared to males in intermediate AMD. However, the mechanisms underlying these differences remain elusive. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and metabolic pathways. Previously, we showed that repression and high-fat diet induce drastic AMD-like phenotypes in mice. Our recent data revealed that repression alone can also induce retinal pigment epithelium (RPE) and retinal dysfunction in mice, and its inhibition results in lipid droplet accumulation in human RPE. Whether sex is a contributing factor in these phenotypes remains to be elucidated. Using electroretinography, we demonstrate that sex could influence RPE function during aging independent of in wild-type (WT) mice. We further show that repression exacerbates RPE and retinal dysfunction in females compared to aged-match male mice. Gene expression analyses revealed that differentially regulates genes related to antioxidant enzymes and mitochondrial dynamics in males and females. RPE flat mounts immunolabeled with TOMM20 and DRP1 indicated a sex-dependent role for in regulating mitochondrial fission. Analyses of mitochondrial network morphology suggested sex-dependent effects of repression on mitochondrial dynamics. Together, our study demonstrates that inhibition of induces a sex-dependent decline in RPE and retinal function in mice. These observations on the sex-dependent regulation of RPE and retinal function could offer novel insights into targeted therapeutic approaches for age-related RPE and retinal degeneration.