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...
| Autores: | ; ; ; ; ; |
|---|---|
| Tipo de documento: | Artículo |
| Estado: | Published version |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad de Sevilla (US) |
| Repositorio: | idUS. Depósito de Investigación de la Universidad de Sevilla |
| OAI Identifier: | oai:idus.us.es:11441/178552 |
| Acceso en línea: | https://hdl.handle.net/11441/178552 https://doi.org/10.1016/j.bbrc.2025.152887 |
| Nivel de acceso: | Acceso abierto |
| Palabra clave: | Mast cells Ageing Lysosomal acidification Ketotifen V-ATPase Endocytosis |
| _version_ | 1878741905884315648 |
|---|---|
| author | Barrella, Lorenzo |
| 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 |
| author_browse | Alés González de la Higuera, Eva María Barrella, Lorenzo Flores Cordero, Juan Antonio Ramírez-Ponce, María Pilar San Millán-Huang, Marta Vázquez Román, María Victoria |
| 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 |
| collection | idUS. Depósito de Investigación de la Universidad de Sevilla |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_ed2ac680ff2e4fd89ebe5b7fe3371a7a |
| institution | Universidad de Sevilla (US) |
| instname_str | Universidad de Sevilla (US) |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:idus.us.es:11441/178552 |
| publishDate | 2025 |
| publishDateSort | 2025 |
| publisher | Academic press inc jnl-comp subscriptions; Academic press inc elsevier science; Elsevier |
| publisherStr | Academic press inc jnl-comp subscriptions; Academic press inc elsevier science; Elsevier |
| reponame_str | idUS. Depósito de Investigación de la Universidad de Sevilla |
| spelling | Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells 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 Mast cells Ageing Lysosomal acidification Ketotifen V-ATPase Endocytosis 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. Academic press inc jnl-comp subscriptions; Academic press inc elsevier science; Elsevier https://hdl.handle.net/11441/178552 https://doi.org/10.1016/j.bbrc.2025.152887 |
| spellingShingle | Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells Barrella, Lorenzo Mast cells Ageing Lysosomal acidification Ketotifen V-ATPase Endocytosis |
| status_str | publishedVersion |
| title | 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_short | Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells |
| title_sort | Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells |
| topic | Mast cells Ageing Lysosomal acidification Ketotifen V-ATPase Endocytosis |
| topic_facet | Mast cells Ageing Lysosomal acidification Ketotifen V-ATPase Endocytosis |
| url | https://hdl.handle.net/11441/178552 https://doi.org/10.1016/j.bbrc.2025.152887 |