Mitochondrial RNA cytosolic leakage drives the SASP
Abstract
Abstract 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.
Article Details
Authors (23)
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