Ambra1 haploinsufficiency in CD1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration

• Published in: Autophagy Vol. 19; no. 3; pp. 784 - 804
• Main Authors: Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Alonso-Gil, Sandra, Mariño, Guillermo, de la Villa, Pedro, Fitze, Patrick S, Fuentes, José Manuel, García-Escudero, Ramón, Ferrington, Deborah A., Gomez-Sintes, Raquel, Boya, Patricia
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 04.03.2023
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Aging; AMBRA1; Animals; autophagy; Autophagy - genetics; Ecosystem; Haploinsufficiency; metabolic alterations; Mice; neurodegeneration; Research Paper; retina; Retina - metabolism; Retinal Degeneration - genetics; retinal pigment epithelium; Retinal Pigment Epithelium - metabolism; autophagy; retina; Aging; metabolic alterations; neurodegeneration; AMBRA1; retinal pigment epithelium
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2022.2103307

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 Ambra1, a pro-autophagic gene. These mice showed protein aggregation in the retina and RPE, metabolic underperformance, and premature vision loss. Moreover, Ambra1 +/gt 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. Abbreviations : 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: NH 4 Cl 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.