Novel duck reovirus σC hijacks the mitochondrial COQ6-CoQ10 axis to drive NLRP3-dependent pyroptosis.

Mitochondrial metabolic homeostasis serves as a critical checkpoint that integrates cellular bioenergetics with innate immunity. While viruses often subvert mitochondrial functions to manipulate cell fate, the specific viral determinants that directly reprogram host metabolic enzymes to drive inflammatory injury remain incompletely defined. Here, using infection with a highly virulent novel duck reovirus (NDRV) strain as a model of systemic immunopathology, we identify the viral capsid protein σC as a metabolic virulence factor. We show that σC binds to the mitochondrial targeting sequence (MTS) of COQ6, a conserved monooxygenase required for coenzyme Q10 (CoQ10) biosynthesis, and blocks its mitochondrial import, thereby disrupting CoQ10 homeostasis. This metabolic blockade induces mitochondrial dysfunction, characterized by mtROS accumulation and the cytosolic release of oxidized mitochondrial DNA (ox-mtDNA). We demonstrate that ox-mtDNA acts as a danger signal that triggers NLRP3 activation and downstream gasdermin E (GSDME)-dependent pyroptosis. Moreover, σC knockdown in infected cells reduces ox-mtDNA release and attenuates pyroptosis. CoQ10 supplementation restores mitochondrial homeostasis and alleviates NDRV-induced inflammatory pathology in vitro and in vivo without detectably reducing viral RNA loads, consistent with a host-directed disease tolerance mechanism. Collectively, these findings define a σC-COQ6-CoQ10-ox-mtDNA-NLRP3 axis that links a structural avian orthoreovirus protein to metabolic reprogramming and highlight the COQ6-CoQ10 pathway as a tractable therapeutic target for limiting virus-induced inflammatory tissue damage.