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, 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

Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. [email protected]. · pubmed

Paper

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.

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Research summary

Mitochondrial RNA leakage activates RNA sensors that drive the senescence-associated secretory phenotype (SASP). This paper is relevant as it addresses a potential root cause of aging by exploring mitochondrial dysfunction and its role in inflammation, which are critical factors in the aging process.

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