Mitochondrial RNA as a broad-spectrum DAMP coordinates antiviral and damage-related immune clearance and confers therapeutic potential

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.