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<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>

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Calcium (Ca2+) fluxes at mitochondria-ER contact sites (MERCS) are a new target of senolysis in therapy-induced senescence (TIS)

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月21日

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  • 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

摘要

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.