Mitochondrial Cholesterol in Alzheimer's Disease and Niemann–Pick Type C Disease

Mitochondrial dysfunction has been recognized as a key player in neurodegenerative diseases, including Alzheimer¿s disease (AD) and Niemann¿Pick type C (NPC) disease. While the pathogenesis of both diseases is different, disruption of intracellular cholesterol trafficking has emerged as a common fea...

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Authors: Torres, Sandra, García-Ruiz, Carmen, Fernández-Checa, José C.
Format: article
Status:Published version
Publication Date:2019
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/201649
Online Access:http://hdl.handle.net/10261/201649
Access Level:Open access
Keyword:Cholesterol
Mitochondria
Lysosomal disorders
Sphingolipids
Acid ceramidase
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spelling Mitochondrial Cholesterol in Alzheimer's Disease and Niemann–Pick Type C DiseaseTorres, SandraGarcía-Ruiz, CarmenFernández-Checa, José C.CholesterolMitochondriaLysosomal disordersSphingolipidsAcid ceramidaseMitochondrial dysfunction has been recognized as a key player in neurodegenerative diseases, including Alzheimer¿s disease (AD) and Niemann¿Pick type C (NPC) disease. While the pathogenesis of both diseases is different, disruption of intracellular cholesterol trafficking has emerged as a common feature of both AD and NPC disease. Nutritional or genetic mitochondrial cholesterol accumulation sensitizes neurons to Ab-mediated neurotoxicity in vitro and promotes cognitive decline in AD models. In addition to the primary accumulation of cholesterol and sphingolipids in lysosomes, NPC disease is also characterized by an increase in mitochondrial cholesterol levels in affected organs, predominantly in brain and liver. In both diseases,mitochondrial cholesterol accumulation disrupts membrane physical properties and restricts the transport of glutathione into mitochondrial matrix, thus impairing the mitochondrial antioxidant defense strategy. The underlying mechanisms leading to mitochondrial cholesterol accumulation in AD and NPC diseases are not fully understood. In the present manuscript, we discuss evidence for the potential role of StARD1 in promoting the trafficking of cholesterol to mitochondria in AD and NPC, whose upregulation involves an endoplasmic reticulum stress and a decrease in acid ceramidase expression, respectively. These findings imply that targeting StARD1 or boosting the mitochondrial antioxidant defense may emerge as a promising approach for both AD and NPC disease.The work was supported by grants SAF2017-85877R and SAF-2015-69944-R from Plan Nacional de I+D, Spain, and by the support of CIBEREHD; the center grant P50-AA-11999 Research Center for Liver and Pancretic Diseases funded by NIAAA/NIH; and support from AGAUR of the Generalitat de Catalunya 2017 SGR1112 and Red Nacional 2018-102799-T de enfermedades metabólicas y cáncer.Frontiers MediaMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Ministerio de Economía y Competitividad (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020192020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/201649reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#SAF2017-85877-R/AEI/10.13039/501100011033info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-85877-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-69944-Rhttp://dx.doi.org/10.3389/fneur.2019.01168Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2016492026-05-22T06:33:51Z
dc.title.none.fl_str_mv Mitochondrial Cholesterol in Alzheimer's Disease and Niemann–Pick Type C Disease
title Mitochondrial Cholesterol in Alzheimer's Disease and Niemann–Pick Type C Disease
spellingShingle Mitochondrial Cholesterol in Alzheimer's Disease and Niemann–Pick Type C Disease
Torres, Sandra
Cholesterol
Mitochondria
Lysosomal disorders
Sphingolipids
Acid ceramidase
title_short Mitochondrial Cholesterol in Alzheimer's Disease and Niemann–Pick Type C Disease
title_full Mitochondrial Cholesterol in Alzheimer's Disease and Niemann–Pick Type C Disease
title_fullStr Mitochondrial Cholesterol in Alzheimer's Disease and Niemann–Pick Type C Disease
title_full_unstemmed Mitochondrial Cholesterol in Alzheimer's Disease and Niemann–Pick Type C Disease
title_sort Mitochondrial Cholesterol in Alzheimer's Disease and Niemann–Pick Type C Disease
dc.creator.none.fl_str_mv Torres, Sandra
García-Ruiz, Carmen
Fernández-Checa, José C.
author Torres, Sandra
author_facet Torres, Sandra
García-Ruiz, Carmen
Fernández-Checa, José C.
author_role author
author2 García-Ruiz, Carmen
Fernández-Checa, José C.
author2_role author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Ministerio de Economía y Competitividad (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cholesterol
Mitochondria
Lysosomal disorders
Sphingolipids
Acid ceramidase
topic Cholesterol
Mitochondria
Lysosomal disorders
Sphingolipids
Acid ceramidase
description Mitochondrial dysfunction has been recognized as a key player in neurodegenerative diseases, including Alzheimer¿s disease (AD) and Niemann¿Pick type C (NPC) disease. While the pathogenesis of both diseases is different, disruption of intracellular cholesterol trafficking has emerged as a common feature of both AD and NPC disease. Nutritional or genetic mitochondrial cholesterol accumulation sensitizes neurons to Ab-mediated neurotoxicity in vitro and promotes cognitive decline in AD models. In addition to the primary accumulation of cholesterol and sphingolipids in lysosomes, NPC disease is also characterized by an increase in mitochondrial cholesterol levels in affected organs, predominantly in brain and liver. In both diseases,mitochondrial cholesterol accumulation disrupts membrane physical properties and restricts the transport of glutathione into mitochondrial matrix, thus impairing the mitochondrial antioxidant defense strategy. The underlying mechanisms leading to mitochondrial cholesterol accumulation in AD and NPC diseases are not fully understood. In the present manuscript, we discuss evidence for the potential role of StARD1 in promoting the trafficking of cholesterol to mitochondria in AD and NPC, whose upregulation involves an endoplasmic reticulum stress and a decrease in acid ceramidase expression, respectively. These findings imply that targeting StARD1 or boosting the mitochondrial antioxidant defense may emerge as a promising approach for both AD and NPC disease.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/201649
url http://hdl.handle.net/10261/201649
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
SAF2017-85877-R/AEI/10.13039/501100011033
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-85877-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-69944-R
http://dx.doi.org/10.3389/fneur.2019.01168
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
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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