Mitochondrial RNA-Type I Interferon Axis in Sjögren's Disease: Molecular Mechanisms and Translational Implications

Sjögren's disease (SjD) is a systemic autoimmune disease characterized by exocrine dysfunction, lymphocytic infiltration of the exocrine glands, and prominent activation of the interferon (IFN) pathway. Although IFN signatures are recognized as a central feature of SjD, endogenous triggers that sustain chronic IFN-driven inflammation remain incompletely understood. Mitochondrial RNAs (mtRNAs), particularly double-stranded species, have recently emerged as immunostimulatory molecules capable of linking mitochondrial stress to innate immune activation. In this review, we discuss the biological basis of mtRNA biogenesis and processing, the formation and mislocalization of mitochondrial double-stranded RNAs, and their recognition by innate immune sensors relevant to induction of type I IFN. We also describe how epithelial stress, mitochondrial dysfunction, and mtRNA accumulation amplify IFN-rich inflammatory circuits and glandular injury in SjD. Experimental studies in salivary gland epithelial models and SjD-relevant tissues support a mechanistic role for the mtRNA-type I IFN axis, while emerging clinical data suggest that extracellular mtRNA levels in saliva and plasma may have potential as biomarkers of disease activity and patient stratification. Although current evidence remains limited, the mtRNA-type I IFN axis provides a biologically plausible link between epithelial stress and immune dysregulation, and may have translational implications in SjD.