Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer disease

Mitochondrial dysfunction is behind several neurodegenerative diseases, including Alzheimer disease (AD). Accumulation of damaged mitochondria is already observed at the early stages of AD and has been linked to impaired mitophagy, but the mechanisms underlying this alteration are still not fully kn...

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Detalles Bibliográficos
Autores: Roca-Agujetas, Vicente, Dios, Cristina de, Abadin, Xenia, Colell Riera, Anna
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/260457
Acceso en línea:http://hdl.handle.net/10261/260457
Access Level:acceso abierto
Palabra clave:Mitophagy
Autophagy
Cholesterol
PINK1
Parkin
Optineurin
Aggresomes
Alzheimer disease
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spelling Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer diseaseRoca-Agujetas, VicenteDios, Cristina deAbadin, XeniaColell Riera, AnnaMitophagyAutophagyCholesterolPINK1ParkinOptineurinAggresomesAlzheimer diseaseMitochondrial dysfunction is behind several neurodegenerative diseases, including Alzheimer disease (AD). Accumulation of damaged mitochondria is already observed at the early stages of AD and has been linked to impaired mitophagy, but the mechanisms underlying this alteration are still not fully known. In our recent study, we show that intracellular cholesterol enrichment can downregulate amyloid beta (Aβ)-induced mitophagy. Mitochondrial glutathione depletion resulting from high cholesterol levels promotes PINK1 (PTEN induced kinase 1)-mediated mitophagosome formation; however, mitophagy flux is ultimately disrupted, most likely due to fusion deficiency of endosomes-lysosomes caused by cholesterol. Meanwhile, in APP-PSEN1-SREBF2 mice, an AD mouse model that overexpresses the cholesterol-related transcription factor SREBF2, cholesterol accumulation prompts an oxidative- and age-dependent cytosolic aggregation of the mitophagy adaptor OPTN (optineurin), which prevents mitophagosome formation despite enhanced PINK1-PRKN/parkin signaling. Hippocampal neurons from postmortem brain of AD individuals reproduce the progressive accumulation of OPTN in aggresome-like structures accompanied by high levels of mitochondrial cholesterol in advanced stages of the disease. Overall, these data provide new insights into the impairment of the PINK1-PRKN mitophagy pathway in AD and suggest the combination of mitophagy inducers with strategies focused on restoring the cholesterol homeostasis and mitochondrial redox balance as a potential disease-modifying therapy for AD.This work was supported by the Fundació la Marató de TV3 [2014-093]; Ministerio de Ciencia, Innovación y Universidades (ES) [RTI2018- 095572-B-100].Peer reviewedTaylor & FrancisFundació La Marató de TV3Ministerio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220212022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/260457reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-095572-B-I00http://dx.doi.org/10.1080/15548627.2021.1920814Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2604572026-05-22T06:33:51Z
dc.title.none.fl_str_mv Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer disease
title Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer disease
spellingShingle Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer disease
Roca-Agujetas, Vicente
Mitophagy
Autophagy
Cholesterol
PINK1
Parkin
Optineurin
Aggresomes
Alzheimer disease
title_short Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer disease
title_full Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer disease
title_fullStr Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer disease
title_full_unstemmed Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer disease
title_sort Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer disease
dc.creator.none.fl_str_mv Roca-Agujetas, Vicente
Dios, Cristina de
Abadin, Xenia
Colell Riera, Anna
author Roca-Agujetas, Vicente
author_facet Roca-Agujetas, Vicente
Dios, Cristina de
Abadin, Xenia
Colell Riera, Anna
author_role author
author2 Dios, Cristina de
Abadin, Xenia
Colell Riera, Anna
author2_role author
author
author
dc.contributor.none.fl_str_mv Fundació La Marató de TV3
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Mitophagy
Autophagy
Cholesterol
PINK1
Parkin
Optineurin
Aggresomes
Alzheimer disease
topic Mitophagy
Autophagy
Cholesterol
PINK1
Parkin
Optineurin
Aggresomes
Alzheimer disease
description Mitochondrial dysfunction is behind several neurodegenerative diseases, including Alzheimer disease (AD). Accumulation of damaged mitochondria is already observed at the early stages of AD and has been linked to impaired mitophagy, but the mechanisms underlying this alteration are still not fully known. In our recent study, we show that intracellular cholesterol enrichment can downregulate amyloid beta (Aβ)-induced mitophagy. Mitochondrial glutathione depletion resulting from high cholesterol levels promotes PINK1 (PTEN induced kinase 1)-mediated mitophagosome formation; however, mitophagy flux is ultimately disrupted, most likely due to fusion deficiency of endosomes-lysosomes caused by cholesterol. Meanwhile, in APP-PSEN1-SREBF2 mice, an AD mouse model that overexpresses the cholesterol-related transcription factor SREBF2, cholesterol accumulation prompts an oxidative- and age-dependent cytosolic aggregation of the mitophagy adaptor OPTN (optineurin), which prevents mitophagosome formation despite enhanced PINK1-PRKN/parkin signaling. Hippocampal neurons from postmortem brain of AD individuals reproduce the progressive accumulation of OPTN in aggresome-like structures accompanied by high levels of mitochondrial cholesterol in advanced stages of the disease. Overall, these data provide new insights into the impairment of the PINK1-PRKN mitophagy pathway in AD and suggest the combination of mitophagy inducers with strategies focused on restoring the cholesterol homeostasis and mitochondrial redox balance as a potential disease-modifying therapy for AD.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/260457
url http://hdl.handle.net/10261/260457
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-095572-B-I00
http://dx.doi.org/10.1080/15548627.2021.1920814
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Taylor & Francis
publisher.none.fl_str_mv Taylor & Francis
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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