Mitochondrial RNA cytosolic leakage drives the SASP
- 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
- Ruben 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
2025-12-15
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.