Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages
| Main Author: | |
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| Publication Date: | 2023 |
| Other Authors: | , , , , , , , , , , , , , , , , , |
| Format: | Article |
| Language: | eng |
| Source: | Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) |
| Download full: | http://hdl.handle.net/10362/166826 |
Summary: | Funding 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. |
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Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophagescholesteryl hemiesterslysosome dysfunctionlysosome exocytosisoxidized low-density lipoproteinsStructural BiologyBiochemistryMolecular BiologyGeneticsCell BiologyFunding 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.A 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.NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)iNOVA4Health - pólo NMSRUNDomingues, NeuzaMarques, André R.A.Calado, Rita Diogo AlmeidaFerreira, InêsRamos, CristianoRamalho, JoséI. L. Soares, MariaPereira, TelmoOliveira, LuísVicente, José R.Wong, Louise H.Simões, Inês C.M.M. V. D. Pinho e Melo, TeresaPeden, AndrewC, Guimas AlmeidaFutter, Clare E.Puertollano, RosaVaz, Winchil L.C.Vieira, Otília V.2024-04-30T23:25:51Z2023-072023-07-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/166826eng1398-9219PURE: 60970598https://doi.org/10.1111/tra.12888info:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2024-05-22T18:20:55Zoai:run.unl.pt:10362/166826Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-28T17:51:44.971496Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse |
| dc.title.none.fl_str_mv |
Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages |
| title |
Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages |
| spellingShingle |
Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages Domingues, Neuza cholesteryl hemiesters lysosome dysfunction lysosome exocytosis oxidized low-density lipoproteins Structural Biology Biochemistry Molecular Biology Genetics Cell Biology |
| title_short |
Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages |
| title_full |
Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages |
| title_fullStr |
Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages |
| title_full_unstemmed |
Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages |
| title_sort |
Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages |
| author |
Domingues, Neuza |
| author_facet |
Domingues, Neuza Marques, André R.A. Calado, Rita Diogo Almeida Ferreira, Inês Ramos, Cristiano Ramalho, José I. L. Soares, Maria Pereira, Telmo Oliveira, Luís Vicente, José R. Wong, Louise H. Simões, Inês C.M. M. V. D. Pinho e Melo, Teresa Peden, Andrew C, Guimas Almeida Futter, Clare E. Puertollano, Rosa Vaz, Winchil L.C. Vieira, Otília V. |
| author_role |
author |
| author2 |
Marques, André R.A. Calado, Rita Diogo Almeida Ferreira, Inês Ramos, Cristiano Ramalho, José I. L. Soares, Maria Pereira, Telmo Oliveira, Luís Vicente, José R. Wong, Louise H. Simões, Inês C.M. M. V. D. Pinho e Melo, Teresa Peden, Andrew C, Guimas Almeida Futter, Clare E. Puertollano, Rosa Vaz, Winchil L.C. Vieira, Otília V. |
| author2_role |
author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM) iNOVA4Health - pólo NMS RUN |
| dc.contributor.author.fl_str_mv |
Domingues, Neuza Marques, André R.A. Calado, Rita Diogo Almeida Ferreira, Inês Ramos, Cristiano Ramalho, José I. L. Soares, Maria Pereira, Telmo Oliveira, Luís Vicente, José R. Wong, Louise H. Simões, Inês C.M. M. V. D. Pinho e Melo, Teresa Peden, Andrew C, Guimas Almeida Futter, Clare E. Puertollano, Rosa Vaz, Winchil L.C. Vieira, Otília V. |
| dc.subject.por.fl_str_mv |
cholesteryl hemiesters lysosome dysfunction lysosome exocytosis oxidized low-density lipoproteins Structural Biology Biochemistry Molecular Biology Genetics Cell Biology |
| topic |
cholesteryl hemiesters lysosome dysfunction lysosome exocytosis oxidized low-density lipoproteins Structural Biology Biochemistry Molecular Biology Genetics Cell Biology |
| description |
Funding 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. |
| publishDate |
2023 |
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2023-07 2023-07-01T00:00:00Z 2024-04-30T23:25:51Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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