Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas Margarita Salas, CSIC, Madrid, Spain.
Department of Functional Biology, University of Oviedo, Spain.
Autophagy. 2023 Mar;19(3):784-804. doi: 10.1080/15548627.2022.2103307. Epub 2022 Jul 24.
Macroautophagy/autophagy is a key process in the maintenance of cellular homeostasis. The age-dependent decline in retinal autophagy has been associated with photoreceptor degeneration. Retinal dysfunction can also result from damage to the retinal pigment epithelium (RPE), as the RPE-retina constitutes an important metabolic ecosystem that must be finely tuned to preserve visual function. While studies of mice lacking essential autophagy genes have revealed a predisposition to retinal degeneration, the consequences of a moderate reduction in autophagy, similar to that which occurs during physiological aging, remain unclear. Here, we described a retinal phenotype consistent with accelerated aging in mice carrying a haploinsufficiency for , a pro-autophagic gene. These mice showed protein aggregation in the retina and RPE, metabolic underperformance, and premature vision loss. Moreover, mice were more prone to retinal degeneration after RPE stress. These findings indicate that autophagy provides crucial support to RPE-retinal metabolism and protects the retina against stress and physiological aging. 4-HNE: 4-hydroxynonenal; AMBRA1: autophagy and beclin 1 regulator 1, AMD: age-related macular degeneration;; GCL: ganglion cell layer; GFAP: glial fibrillary acidic protein; GLUL: glutamine synthetase/glutamate-ammonia ligase; HCL: hierarchical clustering; INL: inner nuclear layer; IPL: inner plexiform layer; LC/GC-MS: liquid chromatography/gas chromatography-mass spectrometry; MA: middle-aged; MTDR: MitoTracker Deep Red; MFI: mean fluorescence intensity; NL: NHCl and leupeptin; Nqo: NAD(P)H quinone dehydrogenase; ONL: outer nuclear layer; OPL: outer plexiform layer; OP: oscillatory potentials; OXPHOS: oxidative phosphorylation; PCR: polymerase chain reaction; PRKC/PKCα: protein kinase C; POS: photoreceptor outer segment; RGC: retinal ganglion cells; RPE: retinal pigment epithelium; SI: sodium iodate; TCA: tricarboxylic acid.
自噬是维持细胞内稳态的关键过程。视网膜自噬随年龄的增长而下降与光感受器变性有关。视网膜功能障碍也可能是由于视网膜色素上皮 (RPE) 损伤引起的，因为 RPE-视网膜构成了一个重要的代谢生态系统，必须精细调节以维持视觉功能。虽然研究缺乏必需自噬基因的小鼠表明易发生视网膜变性，但类似于生理衰老过程中发生的自噬适度减少的后果仍不清楚。在这里，我们描述了携带 基因单倍不足的小鼠的视网膜表型，该基因是一种促进自噬的基因。这些小鼠的视网膜和 RPE 中出现了蛋白质聚集、代谢功能下降和视力丧失提前。此外，RPE 应激后， 小鼠更容易发生视网膜变性。这些发现表明自噬为 RPE-视网膜代谢提供了至关重要的支持，并保护视网膜免受应激和生理衰老的影响。4-HNE：4-羟基壬烯醛；AMBRA1：自噬和 beclin 1 调节因子 1；AMD：年龄相关性黄斑变性；GCL：神经节细胞层；GFAP：神经胶质纤维酸性蛋白；GLUL：谷氨酰胺合成酶/谷氨酸-氨连接酶；HCL：层次聚类；INL：内核层；IPL：内丛状层；LC/GC-MS：液相色谱/气相色谱-质谱法；MA：中年；MTDR：MitoTracker Deep Red；MFI：平均荧光强度；NL：NHCl 和亮抑酶肽；Nqo：NAD(P)H 醌脱氢酶；ONL：外核层；OPL：外丛状层；OP：振荡电位；OXPHOS：氧化磷酸化；PCR：聚合酶链式反应；PRKC/PKCα：蛋白激酶 C；POS：光感受器外段；RGC：视网膜神经节细胞；RPE：视网膜色素上皮；SI：碘酸钠；TCA：三羧酸循环。
