Mitochondrial quality control in non-exudative age-related macular degeneration: From molecular mechanisms to structural and functional recovery

DIEGUEZ, HERNÁN; ROMEO,HORACIO; ALAIMO, AGUSTINA; BERNAL AGUIRRE, NATHALY; CALAMI, JUAN; ADAN AREAN, JUAN SANTIAGO; ALVAREZ, SILVIA; SCIURANO, ROBERTA; ROSENSTEIN, RUTH; DORFMAN, DAMIAN

Free Radical Biology and Medicine

Elsevier Inc.

Año: 2024 vol. 219 p. 17 - 30

and experimental evidence supports that early alterations in macular retinal pigment epithelium (RPE) mitochondriaplay a key role in NE-AMD-induced damage. Mitochondrial dynamics (biogenesis, fusion, fission, andmitophagy), which is under the central control of AMP-activated kinase (AMPK), in turn, determines mitochondrialquality. We have developed a NE-AMD model in C57BL/6J mice induced by unilateral superior cervicalganglionectomy (SCGx), which progressively reproduces the disease hallmarks circumscribed to thetemporal region of the RPE/outer retina that exhibits several characteristics of the human macula. In this workwe have studied RPE mitochondrial structure, dynamics, function, and AMPK role on these parameters’ regulationat the nasal and temporal RPE from control eyes and at an early stage of experimental NE-AMD (i.e., 4weeks post-SCGx). Although RPE mitochondrial mass was preserved, their function, which was higher at thetemporal than at the nasal RPE in control eyes, was significantly decreased at 4 weeks post-SCGx at the sameregion. Mitochondria were bigger, more elongated, and with denser cristae at the temporal RPE from controleyes. Exclusively at the temporal RPE, SCGx severely affected mitochondrial morphology and dynamics, togetherwith the levels of phosphorylated AMPK (p-AMPK). AMPK activation with metformin restored RPE p-AMPKlevels, and mitochondrial dynamics, structure, and function at 4 weeks post-SCGx, as well as visual function andRPE/outer retina structure at 10 weeks post-SCGx. These results demonstrate a key role of the temporal RPEmitochondrial homeostasis as an early target for NE-AMD-induced damage, and that pharmacological AMPKactivation could preserve mitochondrial morphology, dynamics, and function, and, consequently, avoid thefunctional and structural damage induced by NE-AMD.