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.
Authors
- Sandra Rodríguez-López
- Alenka Lovy (ORCID: https://orcid.org/0000-0002-8167-3199)
- Gabriel Quiroz (ORCID: https://orcid.org/0000-0002-1883-886X)
- Galdo Bustos (ORCID: https://orcid.org/0000-0002-4430-4271)
- Armen Zakarian (ORCID: https://orcid.org/0000-0002-9120-1232)
- Eduardo Silva-Pavez (ORCID: https://orcid.org/0000-0002-9650-7521)
- Jordi Molgó (ORCID: https://orcid.org/0000-0002-0693-8994)
- José A. González‐Reyes
- Hernán Huerta (ORCID: https://orcid.org/0000-0002-7392-3311)
- Christian González‐Billault (ORCID: https://orcid.org/0000-0003-0335-1482)
- Marcelo J. Kogan (ORCID: https://orcid.org/0000-0003-0608-5087)
- Edison Salas‐Huenuleo (ORCID: https://orcid.org/0000-0003-4355-5252)
- Andrea Puebla-Huerta
- Sandra A. Niño (ORCID: https://orcid.org/0000-0001-7665-2468)
- Ulises Ahumada-Castro (ORCID: https://orcid.org/0009-0005-5651-7177)
- Tito Calí (ORCID: https://orcid.org/0000-0002-8901-1659)
- Pablo Morgado-Cáceres
- Sergio Linsambarth (ORCID: https://orcid.org/0000-0002-2038-0501)
- José A López-Domínguez (ORCID: https://orcid.org/0000-0001-8733-3294)
- José M. Villalba (ORCID: https://orcid.org/0000-0001-8554-3802)
- Catalina González-Seguel
- Camila Quezada-Gutierez
- César Casanova-Canelo
- Osmán Díaz-Rivera (ORCID: https://orcid.org/0009-0008-0906-1308)
- César Cárdenas (ORCID: https://orcid.org/0000-0003-1115-2790)
Institutions
- Universidad Mayor (CL)
- Centre National de la Recherche Scientifique (FR)
- Buck Institute for Research on Aging (US)
- University of Padua (IT)
- University of California, Santa Barbara (US)
- Universidad de Salamanca (ES)
- SUNY Upstate Medical University (US)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- San Sebastián University (CL)
- Technologies pour la Santé (FR)
- CEA Paris-Saclay (FR)
- Advanced Center for Chronic Diseases (CL)
- Centro de Investigación del Cáncer (ES)
- Center for Climate and Resilience Research (CL)
- University of Córdoba (ES)
- University of Chile (CL)
Publication Details
- Journal
- npj Aging
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1038/s41514-025-00197-1
- Citations
- 7
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Buck Institute for Research on Aging
- Agencia Nacional de Investigación y Desarrollo
- National Institutes of Health
- Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias