Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells

Mast-cell (MC) granules are secretory lysosomes whose function depends on a highly acidic lumen. We asked whether lysosomal pH drifts with age and whether this alteration is reversible. Lysosomal acidification was assessed by quinacrine imaging of peritoneal MCs, which revealed very low fluorescence...

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Autores: Barrella, Lorenzo, Ramírez-Ponce, María Pilar, Vázquez Román, María Victoria, San Millán-Huang, Marta, Flores Cordero, Juan Antonio, Alés González de la Higuera, Eva María
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Recursos:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/178552
Acesso em linha:https://hdl.handle.net/11441/178552
https://doi.org/10.1016/j.bbrc.2025.152887
Access Level:acceso abierto
Palavra-chave:Mast cells
Ageing
Lysosomal acidification
Ketotifen
V-ATPase
Endocytosis
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spelling Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cellsBarrella, LorenzoRamírez-Ponce, María PilarVázquez Román, María VictoriaSan Millán-Huang, MartaFlores Cordero, Juan AntonioAlés González de la Higuera, Eva MaríaMast cellsAgeingLysosomal acidificationKetotifenV-ATPaseEndocytosisMast-cell (MC) granules are secretory lysosomes whose function depends on a highly acidic lumen. We asked whether lysosomal pH drifts with age and whether this alteration is reversible. Lysosomal acidification was assessed by quinacrine imaging of peritoneal MCs, which revealed very low fluorescence in MCs from 2-month-old mice, consistent with immature granules. As MCs matured, quinacrine signal increased, reflecting expansion of the secretory lysosome pool; however, from 15 to 17 months, fluorescence progressively declined, indicating gradual deacidification. Chronic ketotifen treatment restored and amplified the quinacrine signal, enlarged granules, and reduced late-life MC expansion. Acute pharmacological assays revealed that ketotifen's effect requires V-ATPase activity and dynamin-dependent endocytosis. FM1-43 uptake confirmed enhanced endocytic activity with ketotifen. In the brain, ageing led to hypertrophy of toluidine blue–positive MCs without major changes in cell number; five months of ketotifen treatment reversed these morphometric alterations toward a youthful profile. These findings identify lysosomal deacidification as a hallmark of ageing MCs and demonstrate that ketotifen reacidifies secretory lysosomes via V-ATPase and endocytosis-dependent mechanisms, highlighting lysosomal pH control as a tractable strategy to mitigate MC-driven components of inflammaging.Academic press inc jnl-comp subscriptions; Academic press inc elsevier science; ElsevierCitología e Histología Normal y PatológicaBioquímica Médica y Biología Molecular e InmunologíaFisiología Médica y BiofísicaCTS439: Sistema Neuroendocrino DifusoCTS151: Bioquímica MedicaBIO236: Biofísica Celular2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/178552https://doi.org/10.1016/j.bbrc.2025.152887reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésBiochemical and biophysical research communications, 790, 152887.https://www.sciencedirect.com/science/article/pii/S0006291X25016031?via%3Dihubinfo:eu-repo/semantics/openAccessoai:idus.us.es:11441/1785522026-06-17T12:51:07Z
dc.title.none.fl_str_mv Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells
title Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells
spellingShingle Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells
Barrella, Lorenzo
Mast cells
Ageing
Lysosomal acidification
Ketotifen
V-ATPase
Endocytosis
title_short Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells
title_full Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells
title_fullStr Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells
title_full_unstemmed Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells
title_sort Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells
dc.creator.none.fl_str_mv Barrella, Lorenzo
Ramírez-Ponce, María Pilar
Vázquez Román, María Victoria
San Millán-Huang, Marta
Flores Cordero, Juan Antonio
Alés González de la Higuera, Eva María
author Barrella, Lorenzo
author_facet Barrella, Lorenzo
Ramírez-Ponce, María Pilar
Vázquez Román, María Victoria
San Millán-Huang, Marta
Flores Cordero, Juan Antonio
Alés González de la Higuera, Eva María
author_role author
author2 Ramírez-Ponce, María Pilar
Vázquez Román, María Victoria
San Millán-Huang, Marta
Flores Cordero, Juan Antonio
Alés González de la Higuera, Eva María
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Citología e Histología Normal y Patológica
Bioquímica Médica y Biología Molecular e Inmunología
Fisiología Médica y Biofísica
CTS439: Sistema Neuroendocrino Difuso
CTS151: Bioquímica Medica
BIO236: Biofísica Celular
dc.subject.none.fl_str_mv Mast cells
Ageing
Lysosomal acidification
Ketotifen
V-ATPase
Endocytosis
topic Mast cells
Ageing
Lysosomal acidification
Ketotifen
V-ATPase
Endocytosis
description Mast-cell (MC) granules are secretory lysosomes whose function depends on a highly acidic lumen. We asked whether lysosomal pH drifts with age and whether this alteration is reversible. Lysosomal acidification was assessed by quinacrine imaging of peritoneal MCs, which revealed very low fluorescence in MCs from 2-month-old mice, consistent with immature granules. As MCs matured, quinacrine signal increased, reflecting expansion of the secretory lysosome pool; however, from 15 to 17 months, fluorescence progressively declined, indicating gradual deacidification. Chronic ketotifen treatment restored and amplified the quinacrine signal, enlarged granules, and reduced late-life MC expansion. Acute pharmacological assays revealed that ketotifen's effect requires V-ATPase activity and dynamin-dependent endocytosis. FM1-43 uptake confirmed enhanced endocytic activity with ketotifen. In the brain, ageing led to hypertrophy of toluidine blue–positive MCs without major changes in cell number; five months of ketotifen treatment reversed these morphometric alterations toward a youthful profile. These findings identify lysosomal deacidification as a hallmark of ageing MCs and demonstrate that ketotifen reacidifies secretory lysosomes via V-ATPase and endocytosis-dependent mechanisms, highlighting lysosomal pH control as a tractable strategy to mitigate MC-driven components of inflammaging.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/178552
https://doi.org/10.1016/j.bbrc.2025.152887
url https://hdl.handle.net/11441/178552
https://doi.org/10.1016/j.bbrc.2025.152887
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Biochemical and biophysical research communications, 790, 152887.
https://www.sciencedirect.com/science/article/pii/S0006291X25016031?via%3Dihub
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Academic press inc jnl-comp subscriptions; Academic press inc elsevier science; Elsevier
publisher.none.fl_str_mv Academic press inc jnl-comp subscriptions; Academic press inc elsevier science; Elsevier
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.81155

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