Mitochondrial RNA cytosolic leakage drives the SASP
Stella Victorelli, Madeline Eppard, Hélène Martini, Seung‐Hwa Woo, Stacia 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
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.