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<p>Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK play a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction-Associated Steatohepatitis (MASH). These findings highlight mtRNA’s role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.</p>

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Mitochondrial RNA cytosolic leakage drives the SASP

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月15日

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  • Stella Victorelli,
  • Madeline Eppard,
  • Hélène Martini,
  • Seung-Hwa Woo,
  • Stacia P. A. Everts,
  • Gung Lee,
  • Nicholas Pirius,
  • Nuan Han,
  • Eugene Y. Liang,
  • Ana Catarina Franco,
  • Yeaeun Han,
  • Dominik Saul,
  • Eva Nóvoa,
  • Rubén Nogueiras,
  • Patrick L. Splinter,
  • Steven P. O’Hara,
  • Olivia Morgenthaler,
  • Lucía Valenzuela-Pérez,
  • Hyun Se Kim Lee,
  • Diana Jurk,
  • Nicholas F. LaRusso,
  • Petra Hirsova,
  • João F. Passos

摘要

Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK play a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction-Associated Steatohepatitis (MASH). These findings highlight mtRNA’s role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.