Nature communicationsAug 27, 2024

Mitochondrial double-stranded RNA released inside cells may drive inflammation in aging cells

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Mar 14, 2026

Abstract

The release of (mt-dsRNA) into the cytosol is a common characteristic of senescent cells.

mt-dsRNA is linked to the inflammatory response in senescent cells, contributing to their inflammatory secretome.
Inhibition of mitochondrial RNA polymerase and specific dsRNA sensors leads to a decrease in the expression of the inflammatory secretory phenotype.
Senescent cells show heightened sensitivity to mt-dsRNA-driven inflammation due to decreased levels of proteins that typically regulate mt-dsRNA accumulation.
Mitofusin MFN1 plays a significant role in activating the inflammatory response associated with mt-dsRNA, while MFN2 does not.
Inhibition of mitochondrial RNA polymerase can reduce systemic inflammation in conditions related to cellular senescence.

Simplified

The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, we report that the release of mt-dsRNA into the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as (SASP). Inhibition of the mitochondrial RNA polymerase, the dsRNA sensors RIGI and MDA5, or the master inflammatory signaling protein MAVS, all result in reduced expression of the SASP, while broadly preserving other hallmarks of senescence. Moreover, senescent cells are hypersensitized to mt-dsRNA-driven inflammation due to their reduced levels of PNPT1 and ADAR1, two proteins critical for mitigating the accumulation of mt-dsRNA and the inflammatory potency of dsRNA, respectively. We find that mitofusin MFN1, but not MFN2, is important for the activation of the mt-dsRNA/MAVS/SASP axis and, accordingly, genetic or pharmacologic MFN1 inhibition attenuates the SASP. Finally, we report that senescent cells within fibrotic and aged tissues present dsRNA foci, and inhibition of mitochondrial RNA polymerase reduces systemic inflammation associated to senescence. In conclusion, we uncover the mt-dsRNA/MAVS/MFN1 axis as a key driver of the SASP and we identify novel therapeutic strategies for senescence-associated diseases.

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Funding

Competing interests

M.S. is shareholder of Senolytic Therapeutics, Inc., Life Biosciences, Inc., Rejuveron Senescence Therapeutics, AG, and Altos Labs, Inc. M.S. has been consultant, until the end of 2022, of Rejuveron Senescence Therapeutics, AG, and Altos Labs, Inc. M.K. has ongoing or completed research contracts with Galapagos NV, Rejuveron Senescence Therapeutics, and mesoestetic®. E.Z. and E.G. are inventors in patents submitted by Albert Einstein College of Medicine that protect compounds, compositions, and methods for controlling mitofusins for the treatment of diseases and disorders. E.G. has received compensation for consulting and has equity ownership from BaxGen Therapeutics, Comorin Therapeutics, BeanPod Biosciences, Life Biosciences, and Stelexis Biosciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The remaining authors declare no competing interests.

PubMed

Mitochondrial double-stranded RNA released inside cells may drive inflammation in aging cells

Abstract

Full Text

Funding

Competing interests

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