Emerging Lysosomal Functions for Photoreceptor Cell Homeostasis and Survival

Abstract

Lysosomes are membrane-bound cell organelles that respond to nutrient changes and are implicated in cell homeostasis and clearance mechanisms, allowing effective adaptation to specific cellular needs. The relevance of the lysosome has been elucidated in a number of different contexts. Of these, the retina represents an interesting scenario to appreciate the various functions of this organelle in both physiological and pathological conditions. Growing evidence suggests a role for lysosome-related mechanisms in retinal degeneration. Abnormal lysosomal activation or inhibition has dramatic consequences on photoreceptor cell homeostasis and impacts extensive cellular function, which in turn affects vision. Based on these findings, a series of therapeutic methods targeting lysosomal processes could offer treatment for blindness conditions. Here, we review the recent findings on membrane trafficking, subcellular organization, mechanisms by which lysosome/autophagy pathway impairment affects photoreceptor cell homeostasis and the recent advances on developing efficient lysosomal-based therapies for retinal disorders.

The Essential Role of Light-Induced Autophagy in the Inner Choroid/Outer Retinal Neurovascular Unit in Baseline Conditions and Degeneration

“…Similarly, the oxidative metabolism which characterize these cells needs to be supported by an intense turn-over of mitochondria [57][58][59][60]. Again, the need to clear a variety of chemical species requires the support of a massive number of active lysosomes [61][62][63]. The intense generation of structures to be metabolized requires the generation of ceiled, a segregated cell compartment to harvest this obsolete material for delivery to enzymatic clearance.…”

Oxidative stress in the brain and retina after traumatic injury

“…Peroxisomes have been detected within every retinal cell layer, although their distribution is not uniform (Das et al, 2019). Lysosomes have been studied within retinal pigmented epithelial cells (Sinha et al, 2016), linked to photoreceptor cell homeostasis (Santo and Conte, 2021), and lysosomal localization in the retinal pigmented epithelia linked to downstream photoreceptor health (el-Hifnawi et al, 1994). Within the retina, lysosomes appear to be most concentrated in the retinal pigmented epithelia, and are found within photoreceptors (Strauss, 2005).…”

Beyond Genetics: The Role of Metabolism in Photoreceptor Survival, Development and Repair

“…Lysosomes play a critical role in sustaining photoreceptor health and function, beginning with their critical role in phototransduction through their degradation of photoreceptor opsins, including rhodopsin, which must be continually replaced ( Santo and Conte, 2021 ). In addition, circadian cycles of lysosome-mediated autophagy are observed in the rod inner segment following the peak of disc shedding, which is triggered by the constant exposure of photoreceptors to light and subsequent oxidative stress ( Santo and Conte, 2021 ; Reme´ et al, 1986 ).…”

“…Lysosomes play a critical role in sustaining photoreceptor health and function, beginning with their critical role in phototransduction through their degradation of photoreceptor opsins, including rhodopsin, which must be continually replaced ( Santo and Conte, 2021 ). In addition, circadian cycles of lysosome-mediated autophagy are observed in the rod inner segment following the peak of disc shedding, which is triggered by the constant exposure of photoreceptors to light and subsequent oxidative stress ( Santo and Conte, 2021 ; Reme´ et al, 1986 ). Given the important role that lysosomes play in protein and organelle clearing and metabolic sensing, it is not surprising that several lysosomal storage disorders are associated with retinal dystrophies ( Intartaglia et al, 2020 ) and other neurodegenerative diseases ( Zhu et al, 2020 ).…”

“…Indeed, metformin activates AMPK and its protective effects on photoreceptor survival in Rd10 mice, a model of RP, have at least in part been attributed to the activation of lysosome-mediated autophagy ( Xu et al, 2018 ). In addition, an increase in autophagy is seen in a rat model of retinal detachment, and inhibiting autophagy accelerates photoreceptor cell death ( Besirli et al, 2011 ; Santo and Conte, 2021 ). Despite these controversies, which may reflect differences in model systems and assays used, there is a clear link between lysosomal dysfunction and neurodegenerative disorders of the retina.…”