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

DIEGUEZ, HERNÁN H.; ROMEO, HORACIO E.; ALAIMO, AGUSTINA; BERNAL AGUIRRE, NATHALY A.; CALANNI, JUAN S.; ADÁN ARÉAN, JUAN S.; ALVAREZ, SILVIA; SCIURANO, ROBERTA; ROSENSTEIN, RUTH E.; DORFMAN, DAMIÁN

FREE RADICAL BIOLOGY AND MEDICINE

ELSEVIER SCIENCE INC

Año: 2024 vol. 219 p. 17 - 30

0891-5849

Non-exudativeage-related macular degeneration (NE-AMD) is the leading blindness cause in theelderly. Clinical and experimental evidence supports that early alterations inmacular retinal pigment epithelium (RPE) mitochondria play a key role inNE-AMD-induced damage. Mitochondrial dynamics (biogenesis, fusion, fission, andmitophagy), 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/6Jmice induced by unilateral superior cervical ganglionectomy (SCGx), which progressivelyreproduces the disease hallmarks circumscribed to the temporal region of theRPE/outer retina that exhibits several characteristics of the human macula. In this work we have studied RPEmitochondrial structure, dynamics, function, and AMPK role on these parameters’regulation at the nasal and temporal RPE from control eyes and at an earlystage of experimental NE-AMD (i.e., 4 weeks post-SCGx). Although RPE mitochondrial mass was preserved, their function,which was higher at the temporal than at the nasal RPE in control eyes, was significantlydecreased at 4 weeks post-SCGx atthe same region. Mitochondria were bigger, more elongated, and withdenser cristae at the temporal RPE from control eyes. Exclusively at thetemporal RPE, SCGx severely affected mitochondrial morphology and dynamics,together with the levels of phosphorylated AMPK (p-AMPK).AMPKactivation with metformin restored RPE p-AMPK levels, and mitochondrialdynamics, structure, and function at 4 weeks post-SCGx, as well as visualfunction and RPE/outer retina structure at 10 weeks post-SCGx. These resultsdemonstrate a key role of the temporal RPE mitochondrial homeostasis as anearly target for NE-AMD-induced damage, and that pharmacological AMPK activationcould preserve mitochondrial morphology, dynamics, and function, and,consequently, avoid the functional and structural damage induced by NE-AMD.