Mitochondrial quality control in non-exudative age-related macular degeneration : from molecular mechanisms to structural and functional recovery
Abstract: Non-exudative age-related macular degeneration (NE-AMD) is the leading blindness cause in the elderly. Clinical and experimental 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 progressively reproduces the disease hallmarks circumscribed to the temporal region of the RPE/outer retina that exhibits several characteristics of the human macula. In this work we have studied RPE mitochondrial structure, dynamics, function, and AMPK role on these parameters’ regulation at the nasal and temporal RPE from control eyes and at an early stage 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 significantly decreased at 4 weeks post-SCGx at the same region. Mitochondria were bigger, more elongated, and with denser cristae at the temporal RPE from control eyes. Exclusively at the temporal RPE, SCGx severely affected mitochondrial morphology and dynamics, together with the levels of phosphorylated AMPK (p-AMPK). AMPK activation with metformin restored RPE p-AMPK levels, and mitochondrial dynamics, structure, and function at 4 weeks post-SCGx, as well as visual function and RPE/outer retina structure at 10 weeks post-SCGx. These results demonstrate a key role of the temporal RPE mitochondrial homeostasis as an early target for NE-AMD-induced damage, and that pharmacological AMPK activation could preserve mitochondrial morphology, dynamics, and function, and, consequently, avoid the functional and structural damage induced by NE-AMD.
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2024-06-11T17:19:56Z
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oai:ucacris:123456789-182672024-06-13T08:47:03Z Mitochondrial quality control in non-exudative age-related macular degeneration : from molecular mechanisms to structural and functional recovery Dieguez, Hernán H. Romeo, Horacio Alaimo, Agustina Bernal Aguirre, Nathaly Azucena Adán Aréan, Juan S. Álvarez, Silvia Sciurano, Roberta Rosenstein, Ruth E. Dorfman, Damián CELULAS RETINA MITOCONDRIAS METFORMINA Abstract: Non-exudative age-related macular degeneration (NE-AMD) is the leading blindness cause in the elderly. Clinical and experimental 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 progressively reproduces the disease hallmarks circumscribed to the temporal region of the RPE/outer retina that exhibits several characteristics of the human macula. In this work we have studied RPE mitochondrial structure, dynamics, function, and AMPK role on these parameters’ regulation at the nasal and temporal RPE from control eyes and at an early stage 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 significantly decreased at 4 weeks post-SCGx at the same region. Mitochondria were bigger, more elongated, and with denser cristae at the temporal RPE from control eyes. Exclusively at the temporal RPE, SCGx severely affected mitochondrial morphology and dynamics, together with the levels of phosphorylated AMPK (p-AMPK). AMPK activation with metformin restored RPE p-AMPK levels, and mitochondrial dynamics, structure, and function at 4 weeks post-SCGx, as well as visual function and RPE/outer retina structure at 10 weeks post-SCGx. These results demonstrate a key role of the temporal RPE mitochondrial homeostasis as an early target for NE-AMD-induced damage, and that pharmacological AMPK activation could preserve mitochondrial morphology, dynamics, and function, and, consequently, avoid the functional and structural damage induced by NE-AMD. 2024-06-11T17:19:56Z 2024-06-11T17:20:00Z 2024-06-11T17:19:56Z 2024-06-11T17:20:00Z 2024 Artículo Dorfman, D. et al. Mitochondrial quality control in non-exudative age-related macular degeneration : from molecular mechanisms to structural and functional recovery [en línea]. Free radical biology & medicine. 2024, 219. doi: 10.1016/j.freeradbiomed.2024.03.024. Disponible en: https://repositorio.uca.edu.ar/handle/123456789/18267 1873-4596 (impreso) 0891-5849 (online) https://repositorio.uca.edu.ar/handle/123456789/18267 10.1016/j.freeradbiomed.2024.03.024 eng Acceso restringido http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Elsevier Free radical biology & medicine |
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CELULAS RETINA MITOCONDRIAS METFORMINA CELULAS RETINA MITOCONDRIAS METFORMINA Dieguez, Hernán H. Romeo, Horacio Alaimo, Agustina Bernal Aguirre, Nathaly Azucena Adán Aréan, Juan S. Álvarez, Silvia Sciurano, Roberta Rosenstein, Ruth E. Dorfman, Damián Mitochondrial quality control in non-exudative age-related macular degeneration : from molecular mechanisms to structural and functional recovery |
description |
Abstract: Non-exudative age-related macular degeneration (NE-AMD) is the leading blindness cause in the elderly. Clinical
and experimental 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 progressively reproduces the disease hallmarks circumscribed to the
temporal region of the RPE/outer retina that exhibits several characteristics of the human macula. In this work
we have studied RPE mitochondrial structure, dynamics, function, and AMPK role on these parameters’ regulation
at the nasal and temporal RPE from control eyes and at an early stage 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 significantly decreased at 4 weeks post-SCGx at the same
region. Mitochondria were bigger, more elongated, and with denser cristae at the temporal RPE from control
eyes. Exclusively at the temporal RPE, SCGx severely affected mitochondrial morphology and dynamics, together
with the levels of phosphorylated AMPK (p-AMPK). AMPK activation with metformin restored RPE p-AMPK
levels, and mitochondrial dynamics, structure, and function at 4 weeks post-SCGx, as well as visual function and RPE/outer retina structure at 10 weeks post-SCGx. These results demonstrate a key role of the temporal RPE mitochondrial homeostasis as an early target for NE-AMD-induced damage, and that pharmacological AMPK activation could preserve mitochondrial morphology, dynamics, and function, and, consequently, avoid the functional and structural damage induced by NE-AMD. |
format |
Artículo |
topic_facet |
CELULAS RETINA MITOCONDRIAS METFORMINA |
author |
Dieguez, Hernán H. Romeo, Horacio Alaimo, Agustina Bernal Aguirre, Nathaly Azucena Adán Aréan, Juan S. Álvarez, Silvia Sciurano, Roberta Rosenstein, Ruth E. Dorfman, Damián |
author_facet |
Dieguez, Hernán H. Romeo, Horacio Alaimo, Agustina Bernal Aguirre, Nathaly Azucena Adán Aréan, Juan S. Álvarez, Silvia Sciurano, Roberta Rosenstein, Ruth E. Dorfman, Damián |
author_sort |
Dieguez, Hernán H. |
title |
Mitochondrial quality control in non-exudative age-related macular degeneration : from molecular mechanisms to structural and functional recovery |
title_short |
Mitochondrial quality control in non-exudative age-related macular degeneration : from molecular mechanisms to structural and functional recovery |
title_full |
Mitochondrial quality control in non-exudative age-related macular degeneration : from molecular mechanisms to structural and functional recovery |
title_fullStr |
Mitochondrial quality control in non-exudative age-related macular degeneration : from molecular mechanisms to structural and functional recovery |
title_full_unstemmed |
Mitochondrial quality control in non-exudative age-related macular degeneration : from molecular mechanisms to structural and functional recovery |
title_sort |
mitochondrial quality control in non-exudative age-related macular degeneration : from molecular mechanisms to structural and functional recovery |
publisher |
Elsevier |
publishDate |
2024-06-11T17:19:56Z |
url |
https://repositorio.uca.edu.ar/handle/123456789/18267 |
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