Abstract
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 describe a retinal phenotype consistent with accelerated aging in mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene. These mice show protein aggregation in the retina and RPE, metabolic underperformance, and premature vision loss. Moreover, Ambra1+/gt mice are 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵& Shared first authorship
- Abbreviations
- AMD
- age-related macular degeneration
- CNS
- central nervous system
- FACS
- fluorescence-activated cell sorting
- GCL
- ganglion cell layer
- GFAP
- glial fibrillary acidic protein
- GS
- glutamine synthetase
- HCL
- hierarchical clustering
- INL
- inner nuclear layer
- IPL
- inner plexiform layer
- LC/GC-MS
- liquid chromatography/gas chromatography–mass spectrometry
- MA
- middle-aged
- MDTR
- MitoTracker Deep Red
- MFI
- mean fluorescence intensity
- NL
- NH4Cl and leupeptin
- Nqo
- NAD(P)H quinone dehydrogenase
- ONL
- outer nuclear layer
- OPL
- outer plexiform layer
- OP
- oscillatory potentials
- OXPHOS
- oxidative phosphorylation
- PCA
- principal component analysis
- PCR
- polymerase chain reaction
- PKC
- protein kinase C
- PPP
- pentose phosphate pathway
- POS
- photoreceptor outer segment
- PRPP
- phosphoribosyl pyrophosphate
- RGC
- retinal ganglion cells
- RPE
- retinal pigmented epithelium
- SI
- sodium iodate
- TCA
- tricarboxylic acid; 4-HNE: 4-hydroxynonenal