Mitochondrial RNA as a broad-spectrum DAMP coordinates antiviral and damage-related immune clearance and confers therapeutic potential.
5 affiliations
- 1State Key Laboratory of Virology and Biosafety, College of Life Sciences, Wuhan University, Wuhan, China.
- 2Postgraduate Training Base at Shanghai Gongli Hospital, Ningxia Medical University, Shanghai, China.
- 3Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
- 4School of Gongli Hospital Medical Technology, University of Shanghai for Science and Technology, Shanghai, China.
- 5Department of Clinical Laboratory, Pudong Gongli Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, China. [email protected].
Abstract
During viral infection and tissue injury, efficient immune clearance of infected or damaged cells is crucial for host defense and homeostasis. Here, we identify mitochondrial RNA (mtRNA) as a broad-spectrum damage-associated molecular pattern (DAMP) that coordinates antiviral and damage-related immune clearance. Through an integrative approach combining in vitro cellular assays and multi-strain murine models, we demonstrate that viral infection and cellular stress promote POLRMT-dependent mtRNA synthesis and its release into the cytosol through BAX/mPTP-mediated mitochondrial pores. Once released, mtRNA activates the MAVS signaling pathway, triggering a robust type I interferon response that operates independently of the cGAS-STING axis. Notably, viruses exploit a negative feedback loop for immune evasion: type I interferon upregulates the exoribonuclease PNPT1, which degrades cytosolic mtRNA and thereby dampens the mtRNA-MAVS axis. Critically, pharmacological inhibition of PNPT1 with lanthanum chloride (LanC), combined with BH3 mimetics that relieve the BCL-2-mediated blockade of BAX/BAK pores, synergistically reactivates mtRNA release and restores antiviral immunity. This dual strategy demonstrates potent antiviral and anti-fibrotic efficacy in preclinical models without significant toxicity. Our findings establish the mtRNA-MAVS axis as a central, broadly applicable immune surveillance pathway and provide a mechanistic framework for developing therapies that overcome both viral immune evasion and the limitations of current STING-targeted agonists.
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BibTeX
@article{tian2026mitochondrial,
title = {{Mitochondrial RNA as a broad-spectrum DAMP coordinates antiviral and damage-related immune clearance and confers therapeutic potential.}},
author = {Mingfu Tian and Guangli Li and Zelin Chai and Siyu Liu and Zhiqiang Li and Dehua Zhang and Chengliang Zhu and Kailang Wu and Xinghui Liu},
journal = {Cell death \& disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09153-7},
url = {https://europepmc.org/article/MED/42967935},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mitochondrial RNA as a broad-spectrum DAMP coordinates antiviral and damage-related immune clearance and confers therapeutic potential.
AU - Mingfu Tian
AU - Guangli Li
AU - Zelin Chai
AU - Siyu Liu
AU - Zhiqiang Li
AU - Dehua Zhang
AU - Chengliang Zhu
AU - Kailang Wu
AU - Xinghui Liu
PY - 2026
DA - 2026/08/04
JO - Cell death & disease
DO - 10.1038/s41419-026-09153-7
UR - https://europepmc.org/article/MED/42967935
AB - During viral infection and tissue injury, efficient immune clearance of infected or damaged cells is crucial for host defense and homeostasis. Here, we identify mitochondrial RNA (mtRNA) as a broad-spectrum damage-associated molecular pattern (DAMP) that coordinates antiviral and damage-related immune clearance. Through an integrative approach combining in vitro cellular assays and multi-strain murine models, we demonstrate that viral infection and cellular stress promote POLRMT-dependent mtRNA synthesis and its release into the cytosol through BAX/mPTP-mediated mitochondrial pores. Once released, mtRNA activates the MAVS signaling pathway, triggering a robust type I interferon response that operates independently of the cGAS-STING axis. Notably, viruses exploit a negative feedback loop for immune evasion: type I interferon upregulates the exoribonuclease PNPT1, which degrades cytosolic mtRNA and thereby dampens the mtRNA-MAVS axis. Critically, pharmacological inhibition of PNPT1 with lanthanum chloride (LanC), combined with BH3 mimetics that relieve the BCL-2-mediated blockade of BAX/BAK pores, synergistically reactivates mtRNA release and restores antiviral immunity. This dual strategy demonstrates potent antiviral and anti-fibrotic efficacy in preclinical models without significant toxicity. Our findings establish the mtRNA-MAVS axis as a central, broadly applicable immune surveillance pathway and provide a mechanistic framework for developing therapies that overcome both viral immune evasion and the limitations of current STING-targeted agonists.
SN - 2041-4889
ER -