AMPK REGULATES MACULAR RETINAL PIGMENT EPITHELIUM MITOCHONDRIAL HOMEOSTASIS: ROLE IN EARLY NON-EXUDATIVE AGE-RELATED MACULAR DEGENERATION IN MICE

Abstract

Purpose : Non-exudative age-related macular degeneration (NE-AMD) is the leading blindness cause in the elderly. Growing evidence supports that early alterations in macular retinal pigment epithelium (RPE) mitochondria play a key role in NE-AMD-induced damage. Mitochondrial dynamics (biogenesis, fusion, fission, and mitophagy), which is under the central control of AMP-activated kinase (AMPK), in turn, determines mitochondrial quality. We have developed a NE-AMD model in C57BL/6J mice induced by unilateral superior cervical ganglionectomy (SCGx), which reproduces the disease hallmarks, circumscribed to the temporal region of the mouse RPE/outer retina, which exhibits several characteristics of the human macula. The aims of this work were studying the role of AMPK activation on mitochondrial structure, function, and dynamics at the nasal (i.e., extra macula-like) and temporal (i.e., macular-like) RPE in control eyes and analysing the consequences of pharmacological AMPK-activation on NE-AMD-induced retinal damage.

Methods : Adult male C57Bl/6J mice were submitted to unilateral SCGx, whereas the contralateral side was submitted to a sham procedure (control eye). A group of animals were treated with metformin (100 mg/kg) every other day for 4 or 10 weeks. The nasal and temporal RPE phosphorylated AMPK (p-AMPK)/AMPK ratio, as well as mitochondrial function, structure and dynamics were studied in control eyes and at 4 weeks post-SCGx, whereas visual function and retinal histology were assessed at 10 weeks post-SCGx.

Results : The temporal RPE from control eyes had higher p-AMPK/AMPK ratio (p<0.01). SCGx, significantly decreased this parameter, as well as mitochondrial function, structure, and dynamics exclusively at the temporal RPE at 4 weeks post-surgery (p<0.01). Metformin-induced AMPK activation prevented the effects of SCGx on mitochondrial function, structure and dynamics at 4 weeks post-surgery (p<0.01), and the visual function deficit and histological alterations induced by SCGx at 10 weeks post-surgery.

Conclusions : We found regional differences in RPE AMPK activation and mitochondrial homeostasis, which could explain the susceptibility of the macular region to NE-AMD. Moreover, AMPK activation with metformin prevented early mitochondrial alterations and visual and histological damage induced by NE-AMD.

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