Pgc-1α 对视网膜色素上皮和视网膜功能的性别调控

IF 4.2 3区 医学 Q2 NEUROSCIENCES Frontiers in Cellular Neuroscience Pub Date : 2024-09-02 DOI:10.3389/fncel.2024.1442079
Kaan Taskintuna, Mohd Akbar Bhat, Tasneem Shaikh, Jacob Hum, Nady Golestaneh
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引用次数: 0

摘要

老年性黄斑变性(AMD)是影响 60 岁以上人群失明的主要原因。虽然衰老是导致老年黄斑变性的主要因素,但有研究报告称,与年龄匹配的男性相比,女性的老年黄斑变性发病率更高。在中度老年黄斑病变中,女性先天性免疫反应效应蛋白补体因子 B 和因子 I 的水平也高于男性。然而,这些差异背后的机制仍然难以捉摸。过氧化物酶体增殖激活受体γ辅激活子-1α(PGC-1α)是线粒体生物生成和代谢途径的关键调节因子。此前,我们发现 Pgc-1α 抑制和高脂饮食会诱导小鼠出现类似 AMD 的严重表型。我们最近的数据显示,单独抑制 Pgc-1α 也能诱导小鼠视网膜色素上皮(RPE)和视网膜功能障碍,体外抑制 Pgc-1α 会导致人类 RPE 中脂滴堆积。性别是否是导致这些表型的一个因素仍有待阐明。我们利用视网膜电图证明,在野生型(WT)小鼠的衰老过程中,性别对 RPE 功能的影响与 Pgc-1α 无关。我们进一步发现,与年龄匹配的雄性小鼠相比,Pgc-1α的抑制会加剧雌性小鼠的RPE和视网膜功能障碍。基因表达分析表明,在雄性和雌性小鼠中,Pgc-1α对抗氧化酶和线粒体动力学相关基因的调控存在差异。用TOMM20和DRP1免疫标记的RPE平片表明,Pgc-1α在调节线粒体裂变中的作用与性别有关。对线粒体网络形态的分析表明,Pgc-1α抑制对线粒体动力学的影响与性别有关。总之,我们的研究表明,抑制 Pgc-1α 会导致小鼠 RPE 和视网膜功能的下降,而这种下降与性别有关。这些关于 RPE 和视网膜功能的性别依赖性调控的观察结果可为与年龄相关的 RPE 和视网膜退化的靶向治疗方法提供新的见解。
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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.
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来源期刊
CiteScore
7.90
自引率
3.80%
发文量
627
审稿时长
6-12 weeks
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.
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