Selective autophagy plays a protective role against acute and age- related retinal degeneration

Abstract

Objective. Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status, this context requires a tightly-regulated housekeeping system that includes selective mitochondrial autophagy. We want to assess the effects of selective autophagy deficit or induction in the retina given an AMD-like paradigm. Materials and methods. Eyes from Ambra1+/+, Ambra1+/gt and mito-QC mice were analysed using flatmount or cryosection immunostaining. Sodium iodate (SI) was used as a model of AMD-like damage and Urolithin A (UA) as a mitophagy inducer. ARPE-19 human cells were used as an in vitro model and analysed by immunostaining, flow cytometry and RT-qPCR. Bioinformatic analysis of public human datasets was also performed. Results. Ambra1+/gt autophagy-deficient mice present alterations in the RPE, similar to those observed in human AMD patients, such as abnormal morphology or lipofuscin accumulation, which appear in an age-dependent manner. Furthermore, Ambra1+/gt mice are more sensitive to acute SI-induced retinal degeneration than their Ambra+/+ littermates. UA induced mitophagy in vivo and prevented degeneration both in the neuroretina and RPE. This amelioration was also associated with decreased lipid peroxidation, gliosis and increased photoreceptor survival. In vitro, inhibition of mitophagy, or general macroautophagy, abolished this rescue. Conclusions. Selective autophagy plays a protective role in the retina and can be exploited to preserve vision in physiological or pathological conditions.