Recycling the recyclers: lysophagy emerges as a new pharmacological target for retinal degeneration

Abstract

Dysregulated macroautophagy/autophagy is one of the hallmarks of aging and has also been linked to higher incidence of several age-associated diseases such as age-related macular degeneration (AMD). The main cell type affected in AMD is the retinal pigment epithelium (RPE), and this disease can lead to central vision loss. Despite affecting around 8.7% of the population between 45-85 years, its etiopathogenesis remains unknown. In our recent manuscript using the pharmacological sodium iodate (SI) model of AMD we identified severe lysosomal membrane permeabilization (LMP) in the RPE, that leads to autophagy flux blockage and proteostasis defects. Treatment with the natural compound urolithin A (UA) reduces RPE cell death and alleviates vision loss, concurrent with full autophagy restoration. While UA was initially described as a specific mitophagy inducer, we now show that it is also able to promote SQSTM1/p62-dependent lysophagy in the context of lysosomal damage and LMP. Genetic downregulation of SQSTM1/p62 fully abolishes the effect of UA on lysophagy while mitophagy stimulation remains unaffected. In summary, these findings highlight the wide range of pathways modulated by UA and its potential implementation in the management of AMD and other diseases involving lysosomal damage.

Keywords: AMD; RPE; autophagy; lysosomal membrane permeabilization; lysosome.

Figure 1.

Lysophagy mediates the neuroprotective effect of urolithin a (UA) in the sodium iodate (SI) model of AMD-associated geographic atrophy in an SQSTM1/p62-dependent manner. SI induces severe lysosomal membrane permeabilization in vivo and in vitro causing a disruption of autophagic flux and RPE cell death. Treatment with UA stimulates SQSTM1/p62-dependent lysophagy, abrogates autophagy defects and promotes retinal cell survival (RPE, photoreceptors) leading to preserved visual function. Diagram created with BioRender.com.