
==== Front
Res Sq
ResearchSquare
Research Square
2693-5015
American Journal Experts

10.21203/rs.3.rs-4876596/v1
10.21203/rs.3.rs-4876596
preprint
1
Article
Mitochondrial RNA cytosolic leakage drives the SASP
Victorelli Stella https://orcid.org/0000-0001-5573-8019

Eppard Madeline
Woo Seung-Hwa https://orcid.org/0000-0002-9336-4457

Everts Stacia
Martini Helene
Pirius Nicholas
Franco Ana Catarina
Han Yeaeun
Saul Dominik https://orcid.org/0000-0002-0673-3710

Splinter Patrick
O'Hara Steven
Valenzuela-Pérez Lucia https://orcid.org/0000-0002-5145-303X

Lee Hyun Se Kim https://orcid.org/0000-0002-1104-4776

Jurk Diana https://orcid.org/0000-0003-4486-0857

LaRusso Nicholas https://orcid.org/0000-0003-3266-0831

Hirsova Petra https://orcid.org/0000-0003-0494-0924

Passos Joao https://orcid.org/0000-0001-8765-1890

27 8 2024
rs.3.rs-4876596https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
https://www.researchsquare.com/article/rs-4876596/v1
nihpp-rs4876596v1.pdf
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 plays 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.
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