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Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages

2023-07Artigo científico Acesso aberto
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dc.contributor.authorDomingues, Neuza
dc.contributor.authorMarques, André R.A.
dc.contributor.authorCalado, Rita Diogo Almeida
dc.contributor.authorFerreira, Inês S.
dc.contributor.authorFerreira, Inês
dc.contributor.authorRamos, Cristiano
dc.contributor.authorRamalho, José
dc.contributor.authorSoares, Maria I.L.
dc.contributor.authorI. L. Soares, Maria
dc.contributor.authorPereira, Telmo
dc.contributor.authorOliveira, Luís
dc.contributor.authorVicente, José R.
dc.contributor.authorWong, Louise H.
dc.contributor.authorSimões, Inês C.M.
dc.contributor.authorPinho e Melo, Teresa M.V.D.
dc.contributor.authorM. V. D. Pinho e Melo, Teresa
dc.contributor.authorPeden, Andrew
dc.contributor.authorPeden, Andrew
dc.contributor.authorAlmeida, Cláudia Guimas
dc.contributor.authorC, Guimas Almeida
dc.contributor.authorFutter, Clare E.
dc.contributor.authorPuertollano, Rosa
dc.contributor.authorVaz, Winchil L.C.
dc.contributor.authorVieira, Otília V.
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutioniNOVA4Health - pólo NMS
dc.contributor.pblBlackwell Publishing Ltd
dc.date.accessioned2024-04-30T23:25:51Z
dc.date.available2024-04-30T23:25:51Z
dc.date.issued2023-07
dc.descriptionFunding Information: This work was financially supported by FCT (Foundation for Science and Technology of the Portuguese Ministry of Science and Higher Education) through national funds and co‐funded by FEDER under the PT2020 Partnership (Ref. PTDC/MED‐PAT/29395/2017, 2022.01305.PTDC and 2022.03249.PTDC). The Coimbra Chemistry Center (CQC) is supported by the FCT through Project UID/QUI/00313/2019. MSCA‐RISE: “Genetic and Small Molecule Modifiers of Lysosomal Function” (LysoMod), financed by Horizon 2020. Ref 734825. Twinning on “Excel in Rare Diseases' Research: Focus on LYSOsomal Disorders and CILiopathies”, Ref (H2020‐TWINN‐2017: GA 81108). Neuza Domingues was a holder of PhD fellowship from the FCT (Ref. No: SFRH/BD/51877/2012), attributed by Inter‐University Doctoral Programme in Ageing and Chronic Disease (PhDOC). André R.A. Marques was funded by the FCT Stimulus of Scientific Employment Individual Support Call 2017 (CEECIND/01006/2017). Rosa Puertollano was funded by the NHLBI Division of Intramural Research (ZIA HL006151‐10). Publisher Copyright: © 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
dc.description.abstractA key event in atherogenesis is the formation of lipid-loaded macrophages, lipidotic cells, which exhibit irreversible accumulation of undigested modified low-density lipoproteins (LDL) in lysosomes. This event culminates in the loss of cell homeostasis, inflammation, and cell death. Nevertheless, the exact chemical etiology of atherogenesis and the molecular and cellular mechanisms responsible for the impairment of lysosome function in plaque macrophages are still unknown. Here, we demonstrate that macrophages exposed to cholesteryl hemiazelate (ChA), one of the most prevalent products of LDL-derived cholesteryl ester oxidation, exhibit enlarged peripheral dysfunctional lysosomes full of undigested ChA and neutral lipids. Both lysosome area and accumulation of neutral lipids are partially irreversible. Interestingly, the dysfunctional peripheral lysosomes are more prone to fuse with the plasma membrane, secreting their undigested luminal content into the extracellular milieu with potential consequences for the pathology. We further demonstrate that this phenotype is mechanistically linked to the nuclear translocation of the MiT/TFE family of transcription factors. The induction of lysosome biogenesis by ChA appears to partially protect macrophages from lipid-induced cytotoxicity. In sum, our data show that ChA is involved in the etiology of lysosome dysfunction and promotes the exocytosis of these organelles. This latter event is a new mechanism that may be important in the pathogenesis of atherosclerosis.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent25886924
dc.identifier.doi10.1111/tra.12888
dc.identifier.issn1398-9219
dc.identifier.otherPURE: 60970598
dc.identifier.otherPURE UUID: 8b072d87-374e-45cb-bc82-facfafccadc5
dc.identifier.otherScopus: 85158007022
dc.identifier.otherPubMed: 37129279
dc.identifier.otherORCID: /0000-0001-9384-2896/work/202047843
dc.identifier.urihttp://hdl.handle.net/10362/166826
dc.identifier.urlhttps://www.scopus.com/pages/publications/85158007022
dc.language.isoeng
dc.peerreviewedyes
dc.subjectcholesteryl hemiesters
dc.subjectlysosome dysfunction
dc.subjectlysosome exocytosis
dc.subjectoxidized low-density lipoproteins
dc.subjectStructural Biology
dc.subjectBiochemistry
dc.subjectMolecular Biology
dc.subjectGenetics
dc.subjectCell Biology
dc.titleOxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophagesen
dc.typejournal article
degois.publication.firstPage284
degois.publication.issue7
degois.publication.lastPage307
degois.publication.titleTraffic
degois.publication.volume24
dspace.entity.typePublication
person.familyNameFerreira
person.familyNameSoares
person.familyNamePinho e Melo
person.familyNamePeden
person.familyNameGuimas Almeida
person.givenNameInês
person.givenNameMaria
person.givenNameTeresa
person.givenNameAndrew
person.givenNameClaudia
person.identifier2511188
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person.identifier.scopus-author-id7203087057
person.identifier.scopus-author-id7003349455
person.identifier.scopus-author-id8082942000
rcaap.rightsopenAccess
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