RETINAL PIGMENT EPITHELIUM MITOCHONDRIAL HOMEOSTASIS IN EARLY NON-EXUDATIVE AGE-RELATED MACULAR DEGENERATION

Abstract

Purpose : Non-exudative age-related macular degeneration (NE-AMD) is the leading cause of irreversible blindness in developed countries. Growing evidence supports that retinal pigment epithelium (RPE) mitochondria dysfunction has a central role in NE-AMD onset and progression. Given that NE-AMD only affects the macula, understanding the regional characteristics making the macula particularly susceptible, is an asset for elucidating NE-AMD pathogenesis. Although rodents lack a macula, a central area with macula-like characteristics, located at the central temporal retina, was described in C57BL/6J mice. We have developed a model of NE-AMD in C57Bl/6J mice, induced by unilateral superior cervical ganglionectomy (SCGx), which reproduces the central hallmarks of the disease, localized at the temporal region of the mouse retina. The aims of this work were comparing mitochondrial structure, function, and dynamics between the nasal (i.e., extra macula-like) and temporal (i.e., macular-like) RPE in control eyes, as well as the effects of early NE-AMD on these parameters.

Methods : Adult male C57Bl/6J mice were submitted to unilateral SCGx, whereas the contralateral side was submitted to a sham procedure (control eye). The nasal and temporal RPE mitochondrial mass, structure, function and dynamics were studied (by super-resolution confocal microscopy, electron microscopy, Western blot, and ATP production rate) in control and SCGx treated eyes at 4 weeks post-SCGx. Two-way ANOVA Tukey test was performed.

Results : The temporal RPE from control eyes had higher ATP production rate; mitochondria were organised in larger clusters, and mitochondria dynamics (biogenesis, fusion, fission and mitophagy) was higher than at the nasal RPE from control eyes (p<0.01). Moreover, the temporal RPE from control eyes had higher mitochondrial proximity, elongation factor, cristae width and density than the nasal RPE (p<0.01). SCGx, which had no effects on mitochondrial mass, significantly decreased ATP production rate, mitochondrial structure, clustering, and dynamics, exclusively at the temporal RPE (p<0.01).

Conclusions : We found regional differences in RPE mitochondrial structure, function and dynamics, which could explain the susceptibility of the macular region to NE-AMD. Moreover, our findings support RPE mitochondrial homeostasis as an early target for NE-AMD-induced damage.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.