Mitochondrial RNA cytosolic leakage drives the SASP.

Autor: Victorelli S; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA., Eppard M; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA., Woo SH; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA., Everts SPA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA., Martini H; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA., Pirius N; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA., Franco AC; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA., Han Y; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA., Saul D; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA., Splinter PL; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA., O'Hara SP; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA., Valenzuela-Pérez L; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA., Lee HSK; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA., Jurk D; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA., LaRusso NF; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA., Hirsova P; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA., Passos JF; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Jazyk: angličtina
Zdroj: Research square [Res Sq] 2024 Aug 27. Date of Electronic Publication: 2024 Aug 27.
DOI: 10.21203/rs.3.rs-4876596/v1
Abstrakt: 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.
Databáze: MEDLINE