Andrea Puebla-Huerta, Hernán Huerta, Camila Quezada-Gutierez, Pablo Morgado-Cáceres, César Casanova-Canelo, Sandra A Niño, Sergio Linsambarth, Osman Díaz-Rivera, José Alberto López-Domínguez, Sandra Rodríguez-López, José Antonio González-Reyes, Galdo Bustos, Eduardo Silva-Pavez, Alenka Lovy, Gabriel Quiroz, Catalina González-Seguel, Edison Salas-Huenuleo, Marcelo J Kogan, Jordi Molgó, Armen Zakarian, José M Villalba, Christian Gonzalez-Billault, Tito Calì, Ulises Ahumada-Castro, J César Cárdenas
{"title":"线粒体-内质网接触部位（MERCS）的钙（Ca2+）通量是治疗性衰老（TIS）中衰老溶解的新靶点。","authors":"Andrea Puebla-Huerta, Hernán Huerta, Camila Quezada-Gutierez, Pablo Morgado-Cáceres, César Casanova-Canelo, Sandra A Niño, Sergio Linsambarth, Osman Díaz-Rivera, José Alberto López-Domínguez, Sandra Rodríguez-López, José Antonio González-Reyes, Galdo Bustos, Eduardo Silva-Pavez, Alenka Lovy, Gabriel Quiroz, Catalina González-Seguel, Edison Salas-Huenuleo, Marcelo J Kogan, Jordi Molgó, Armen Zakarian, José M Villalba, Christian Gonzalez-Billault, Tito Calì, Ulises Ahumada-Castro, J César Cárdenas","doi":"10.1038/s41514-025-00197-1","DOIUrl":null,"url":null,"abstract":"<p><p>Therapy-induced senescence (TIS) alters calcium (Ca²⁺) flux and Mitochondria-ER Contact Sites (MERCS), revealing critical vulnerabilities in senescent cells. In this study, TIS was induced using Doxorubicin and Etoposide, resulting in an increased MERCS contact surface but a significant reduction in ER-mitochondria Ca²⁺ flux. Mechanistically, TIS cells exhibit decreased expression of IP3R isoforms and reduced interaction between type 1 IP3R and VDAC1, impairing Ca²⁺ transfer. This flux is crucial for maintaining the viability of senescent cells, highlighting its potential as a therapeutic target. Inhibition of ER-mitochondria Ca²⁺ flux demonstrates senolytic effects both in vitro and in vivo, offering a novel strategy for targeting senescent cells.</p>","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"11 1","pages":"11"},"PeriodicalIF":4.1000,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845618/pdf/","citationCount":"0","resultStr":"{\"title\":\"Calcium (Ca<sup>2+</sup>) fluxes at mitochondria-ER contact sites (MERCS) are a new target of senolysis in therapy-induced senescence (TIS).\",\"authors\":\"Andrea Puebla-Huerta, Hernán Huerta, Camila Quezada-Gutierez, Pablo Morgado-Cáceres, César Casanova-Canelo, Sandra A Niño, Sergio Linsambarth, Osman Díaz-Rivera, José Alberto López-Domínguez, Sandra Rodríguez-López, José Antonio González-Reyes, Galdo Bustos, Eduardo Silva-Pavez, Alenka Lovy, Gabriel Quiroz, Catalina González-Seguel, Edison Salas-Huenuleo, Marcelo J Kogan, Jordi Molgó, Armen Zakarian, José M Villalba, Christian Gonzalez-Billault, Tito Calì, Ulises Ahumada-Castro, J César Cárdenas\",\"doi\":\"10.1038/s41514-025-00197-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Therapy-induced senescence (TIS) alters calcium (Ca²⁺) flux and Mitochondria-ER Contact Sites (MERCS), revealing critical vulnerabilities in senescent cells. In this study, TIS was induced using Doxorubicin and Etoposide, resulting in an increased MERCS contact surface but a significant reduction in ER-mitochondria Ca²⁺ flux. Mechanistically, TIS cells exhibit decreased expression of IP3R isoforms and reduced interaction between type 1 IP3R and VDAC1, impairing Ca²⁺ transfer. This flux is crucial for maintaining the viability of senescent cells, highlighting its potential as a therapeutic target. Inhibition of ER-mitochondria Ca²⁺ flux demonstrates senolytic effects both in vitro and in vivo, offering a novel strategy for targeting senescent cells.</p>\",\"PeriodicalId\":94160,\"journal\":{\"name\":\"npj aging\",\"volume\":\"11 1\",\"pages\":\"11\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2025-02-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845618/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"npj aging\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1038/s41514-025-00197-1\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GERIATRICS & GERONTOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"npj aging","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1038/s41514-025-00197-1","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}
Calcium (Ca2+) fluxes at mitochondria-ER contact sites (MERCS) are a new target of senolysis in therapy-induced senescence (TIS).
Therapy-induced senescence (TIS) alters calcium (Ca²⁺) flux and Mitochondria-ER Contact Sites (MERCS), revealing critical vulnerabilities in senescent cells. In this study, TIS was induced using Doxorubicin and Etoposide, resulting in an increased MERCS contact surface but a significant reduction in ER-mitochondria Ca²⁺ flux. Mechanistically, TIS cells exhibit decreased expression of IP3R isoforms and reduced interaction between type 1 IP3R and VDAC1, impairing Ca²⁺ transfer. This flux is crucial for maintaining the viability of senescent cells, highlighting its potential as a therapeutic target. Inhibition of ER-mitochondria Ca²⁺ flux demonstrates senolytic effects both in vitro and in vivo, offering a novel strategy for targeting senescent cells.
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