Calcium (Ca2+) fluxes at mitochondria-ER contact sites (MERCS) are a new target of senolysis in therapy-induced senescence (TIS)
Year: 2025
Type: article
Abstract: 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.
Source: npj Aging
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
Institutions: Universidad Mayor, University of Chile, Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer de Salamanca, University of Córdoba, San Sebastián University, SUNY Upstate Medical University, Advanced Center for Chronic Diseases, Centre National de la Recherche Scientifique, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, CEA Paris-Saclay, Médicaments et Technologies pour la Santé, University of California, Santa Barbara, Buck Institute for Research on Aging, University of Padua
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,690
Funders: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Buck Institute for Research on Aging, Agencia Nacional de Investigación y Desarrollo, National Institutes of Health, Fondo Nacional de Desarrollo Científico y Tecnológico, Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias
Awards: G103627852, G162393497, G1890105052, G2200897948, CONSTITUTIVE INSP3R-MEDIATED CALCIUM TRANSFER TO THE MITOCHONDRIA AS A SPECIFIC VULNERABILITY OF SENESCENT CELLS- EFFECT ON CANCER RELAPSE., CENTRO DE GEROCIENCIA SALUD MENTAL Y METABOLISMO (GERO), G50374406, IP3R DISENGAGEMENT FROM MITOCHONDRIAL-ENDOPLASMIC RETICULUM CONTACT SITES (MERCS) ACTIVATE MITOCHONDRIAL RETROGRADE SIGNALS THAT INITIATE THE THERAPY INDUCE SENESCENCE PROGRAM., G5860405644, G633929842, PARTIAL INHIBITION OF IP3R BY NEW SYNTHETIC INHIBITORS PREVENT CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY, BCL-XL/BCL-W REGULATES MITOCHONDRIAL CA2+ UPTAKE AS SURVIVAL MECHANISM IN THERAPY-INDUCED SENESCENCE AND THERAPY-INDUCED SENESCENCE-LIKE PHENOTYPE, THE ROLE OF COMPLEX I/AMPK/BETA1-INTEGRIN PATHWAY ON THE EXTRACELLULAR MATRIX (ECM)-DETACHMENT AND THEIR IMPLICATION IN BREAST CANCER METASTASIS, CENTRO DE ESTUDIOS AVANZADOS DE ENFERMEDADES CRONICAS (ACCDIS), G8536723156, G883642430, CONNEXIN 43 HEMICHANNEL CONTRIBUTE TO THE PROPAGATION OF THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP), G945209877, G99091514
OpenAlex ID: W4407843229