Sex-dependent regulation of retinal pigment epithelium and retinal function by Pgc-1α

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 <i>Pgc-1α</i> repression and high-fat diet induce drastic AMD-like phenotypes in mice. Our recent data revealed that <i>Pgc-1α</i> repression alone can also induce retinal pigment epithelium (RPE) and retinal dysfunction in mice, and its inhibition <i>in vitro</i> 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 <i>Pgc-1α</i> in wild-type (WT) mice. We further show that <i>Pgc-1α</i> repression exacerbates RPE and retinal dysfunction in females compared to aged-match male mice. Gene expression analyses revealed that <i>Pgc-1α</i> 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 <i>Pgc-1α</i> in regulating mitochondrial fission. Analyses of mitochondrial network morphology suggested sex-dependent effects of <i>Pgc-1α</i> repression on mitochondrial dynamics. Together, our study demonstrates that inhibition of <i>Pgc-1α</i> 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.