Mitochondrial-Damaged Salivary Ductal Cells Drive Tls In Pss

To elucidate epithelial-immune crosstalk mechanisms driving salivary gland dysfunction and inflammation in Primary Sjögren's syndrome (pSS). We used single-cell RNA sequencing analysis to profile the mitochondrial gene expression characteristics of salivary gland epithelial cells (SGECs) subpopulations in patients with pSS, and spatial transcriptomics to investigate the spatial relationship between SGEC subpopulations exhibiting mitochondrial damage and immune cells. Immunohistology and multiplex immunofluorescence further validated the novel SGEC subpopulations and marker genes of interest. We identify mitochondrial dysregulation in SGECs as a key driver of immune activation in pSS pathogenesis.Based on the presence of tertiary lymphoid structures (TLSs) as determined by histological examination, the patients were categorized into pSS-TLS and pSS–non-TLS groups. Multi-omics analysis revealed 21 distinct cell populations, including six glandular and three ductal subpopulations, with striated duct cells exhibiting pronounced mitochondrial damage. Mitochondrial dysfunction was predominantly observed in pSS-TLS ductal cells, activating mitochondrial damage-associated molecular pattern (mtDAMP) pathways and promoting immune cell recruitment. Spatial mapping demonstrated that immune cell infiltration even TLS formation in pSS-affected glands was primarily localized around ducts exhibiting mitochondrial damage in SGECs. The spatial organization of the glandular microenvironment revealed a strong correlation between mitochondrial damage in ductal cells and immune cell infiltration, suggesting a mechanistic link between epithelial cell dysfunction and immune activation. These findings establish a critical connection between SGEC mitochondrial abnormalities and inflammatory responses in pSS pathogenesis, providing novel insights into potential therapeutic strategies targeting mitochondrial function to mitigate pSS progression.