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

IF 4.1 Q2 GERIATRICS & GERONTOLOGY

npj aging Pub Date : 2025-02-21 DOI:10.1038/s41514-025-00197-1

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 Cali, Ulises Ahumada-Castro, J César Cárdenas

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引用次数: 0

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.

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治疗诱导衰老（TIS）会改变钙（Ca²⁺）通量和线粒体-ER接触点（MERCS），揭示衰老细胞的关键漏洞。在这项研究中，使用多柔比星和依托泊苷诱导 TIS，结果 MERCS 接触面增加，但 ER 线粒体 Ca²⁺ 通量显著减少。从机理上讲，TIS 细胞表现出 IP3R 异构体表达减少，1 型 IP3R 与 VDAC1 之间的相互作用减少，从而影响了 Ca²⁺ 的转移。这种通量对维持衰老细胞的活力至关重要，突出了其作为治疗靶点的潜力。抑制ER-线粒体Ca²⁺通量在体外和体内都有溶解衰老的作用，为靶向衰老细胞提供了一种新策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

npj aging

CiteScore

8.90

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0.00%

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