Kaan Taskintuna, Mohd Akbar Bhat, Tasneem Shaikh, Jacob Hum, Nady Golestaneh
{"title":"Pgc-1α 对视网膜色素上皮和视网膜功能的性别调控","authors":"Kaan Taskintuna, Mohd Akbar Bhat, Tasneem Shaikh, Jacob Hum, Nady Golestaneh","doi":"10.3389/fncel.2024.1442079","DOIUrl":null,"url":null,"abstract":"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 <jats:italic>Pgc-1α</jats:italic> repression and high-fat diet induce drastic AMD-like phenotypes in mice. Our recent data revealed that <jats:italic>Pgc-1α</jats:italic> repression alone can also induce retinal pigment epithelium (RPE) and retinal dysfunction in mice, and its inhibition <jats:italic>in vitro</jats:italic> 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 <jats:italic>Pgc-1α</jats:italic> in wild-type (WT) mice. We further show that <jats:italic>Pgc-1α</jats:italic> repression exacerbates RPE and retinal dysfunction in females compared to aged-match male mice. Gene expression analyses revealed that <jats:italic>Pgc-1α</jats:italic> 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 <jats:italic>Pgc-1α</jats:italic> in regulating mitochondrial fission. Analyses of mitochondrial network morphology suggested sex-dependent effects of <jats:italic>Pgc-1α</jats:italic> repression on mitochondrial dynamics. Together, our study demonstrates that inhibition of <jats:italic>Pgc-1α</jats:italic> 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.","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2000,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Sex-dependent regulation of retinal pigment epithelium and retinal function by Pgc-1α\",\"authors\":\"Kaan Taskintuna, Mohd Akbar Bhat, Tasneem Shaikh, Jacob Hum, Nady Golestaneh\",\"doi\":\"10.3389/fncel.2024.1442079\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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 <jats:italic>Pgc-1α</jats:italic> repression and high-fat diet induce drastic AMD-like phenotypes in mice. Our recent data revealed that <jats:italic>Pgc-1α</jats:italic> repression alone can also induce retinal pigment epithelium (RPE) and retinal dysfunction in mice, and its inhibition <jats:italic>in vitro</jats:italic> 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 <jats:italic>Pgc-1α</jats:italic> in wild-type (WT) mice. We further show that <jats:italic>Pgc-1α</jats:italic> repression exacerbates RPE and retinal dysfunction in females compared to aged-match male mice. Gene expression analyses revealed that <jats:italic>Pgc-1α</jats:italic> 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 <jats:italic>Pgc-1α</jats:italic> in regulating mitochondrial fission. Analyses of mitochondrial network morphology suggested sex-dependent effects of <jats:italic>Pgc-1α</jats:italic> repression on mitochondrial dynamics. Together, our study demonstrates that inhibition of <jats:italic>Pgc-1α</jats:italic> induces a sex-dependent decline in RPE and retinal function in mice. 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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 Pgc-1α repression and high-fat diet induce drastic AMD-like phenotypes in mice. Our recent data revealed that Pgc-1α repression alone can also induce retinal pigment epithelium (RPE) and retinal dysfunction in mice, and its inhibition in vitro 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 Pgc-1α in wild-type (WT) mice. We further show that Pgc-1α repression exacerbates RPE and retinal dysfunction in females compared to aged-match male mice. Gene expression analyses revealed that Pgc-1α 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 Pgc-1α in regulating mitochondrial fission. Analyses of mitochondrial network morphology suggested sex-dependent effects of Pgc-1α repression on mitochondrial dynamics. Together, our study demonstrates that inhibition of Pgc-1α 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.
期刊介绍:
Frontiers in Cellular Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the cellular mechanisms underlying cell function in the nervous system across all species. Specialty Chief Editors Egidio D‘Angelo at the University of Pavia and Christian Hansel at the University of Chicago are supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.