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

Autor:	Taskintuna K; Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, United States.; Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, United States., Bhat MA; Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, United States., Shaikh T; Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, United States., Hum J; Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, United States., Golestaneh N; Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, United States.; Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, United States.; Department of Neurology, Georgetown University Medical Center, Washington, DC, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in cellular neuroscience [Front Cell Neurosci] 2024 Sep 02; Vol. 18, pp. 1442079. Date of Electronic Publication: 2024 Sep 02 (Print Publication: 2024).
DOI:	10.3389/fncel.2024.1442079
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Taskintuna, Bhat, Shaikh, Hum and Golestaneh.)
Databáze:	MEDLINE
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