Cargando…
Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models
Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760163/ https://www.ncbi.nlm.nih.gov/pubmed/33260715 http://dx.doi.org/10.3390/cells9122552 |
_version_ | 1783627268292083712 |
---|---|
author | Leal, Nuno Santos Dentoni, Giacomo Schreiner, Bernadette Naia, Luana Piras, Antonio Graff, Caroline Cattaneo, Antonio Meli, Giovanni Hamasaki, Maho Nilsson, Per Ankarcrona, Maria |
author_facet | Leal, Nuno Santos Dentoni, Giacomo Schreiner, Bernadette Naia, Luana Piras, Antonio Graff, Caroline Cattaneo, Antonio Meli, Giovanni Hamasaki, Maho Nilsson, Per Ankarcrona, Maria |
author_sort | Leal, Nuno Santos |
collection | PubMed |
description | Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER–mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD. |
format | Online Article Text |
id | pubmed-7760163 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-77601632020-12-26 Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models Leal, Nuno Santos Dentoni, Giacomo Schreiner, Bernadette Naia, Luana Piras, Antonio Graff, Caroline Cattaneo, Antonio Meli, Giovanni Hamasaki, Maho Nilsson, Per Ankarcrona, Maria Cells Article Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER–mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD. MDPI 2020-11-28 /pmc/articles/PMC7760163/ /pubmed/33260715 http://dx.doi.org/10.3390/cells9122552 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Leal, Nuno Santos Dentoni, Giacomo Schreiner, Bernadette Naia, Luana Piras, Antonio Graff, Caroline Cattaneo, Antonio Meli, Giovanni Hamasaki, Maho Nilsson, Per Ankarcrona, Maria Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models |
title | Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models |
title_full | Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models |
title_fullStr | Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models |
title_full_unstemmed | Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models |
title_short | Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models |
title_sort | amyloid β-peptide increases mitochondria-endoplasmic reticulum contact altering mitochondrial function and autophagosome formation in alzheimer’s disease-related models |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760163/ https://www.ncbi.nlm.nih.gov/pubmed/33260715 http://dx.doi.org/10.3390/cells9122552 |
work_keys_str_mv | AT lealnunosantos amyloidbpeptideincreasesmitochondriaendoplasmicreticulumcontactalteringmitochondrialfunctionandautophagosomeformationinalzheimersdiseaserelatedmodels AT dentonigiacomo amyloidbpeptideincreasesmitochondriaendoplasmicreticulumcontactalteringmitochondrialfunctionandautophagosomeformationinalzheimersdiseaserelatedmodels AT schreinerbernadette amyloidbpeptideincreasesmitochondriaendoplasmicreticulumcontactalteringmitochondrialfunctionandautophagosomeformationinalzheimersdiseaserelatedmodels AT naialuana amyloidbpeptideincreasesmitochondriaendoplasmicreticulumcontactalteringmitochondrialfunctionandautophagosomeformationinalzheimersdiseaserelatedmodels AT pirasantonio amyloidbpeptideincreasesmitochondriaendoplasmicreticulumcontactalteringmitochondrialfunctionandautophagosomeformationinalzheimersdiseaserelatedmodels AT graffcaroline amyloidbpeptideincreasesmitochondriaendoplasmicreticulumcontactalteringmitochondrialfunctionandautophagosomeformationinalzheimersdiseaserelatedmodels AT cattaneoantonio amyloidbpeptideincreasesmitochondriaendoplasmicreticulumcontactalteringmitochondrialfunctionandautophagosomeformationinalzheimersdiseaserelatedmodels AT meligiovanni amyloidbpeptideincreasesmitochondriaendoplasmicreticulumcontactalteringmitochondrialfunctionandautophagosomeformationinalzheimersdiseaserelatedmodels AT hamasakimaho amyloidbpeptideincreasesmitochondriaendoplasmicreticulumcontactalteringmitochondrialfunctionandautophagosomeformationinalzheimersdiseaserelatedmodels AT nilssonper amyloidbpeptideincreasesmitochondriaendoplasmicreticulumcontactalteringmitochondrialfunctionandautophagosomeformationinalzheimersdiseaserelatedmodels AT ankarcronamaria amyloidbpeptideincreasesmitochondriaendoplasmicreticulumcontactalteringmitochondrialfunctionandautophagosomeformationinalzheimersdiseaserelatedmodels |