Dysregulated Ca²⁺ signaling, fluid secretion, and mitochondrial function in a mouse model of early Sjögren's disease

The molecular mechanisms leading to saliva secretion are largely established, but factors that underlie secretory hypofunction, specifically related to the autoimmune disease Sjögren's syndrome (SS) are not fully understood. A major conundrum is the lack of association between the severity of salivary gland immune cell infiltration and glandular hypofunction. SS-like disease was induced by treatment with DMXAA, a small molecule agonist of murine STING. We have previously shown that the extent of salivary secretion is correlated with the magnitude of intracellular Ca²⁺ signals (Takano et al., 2021). Contrary to our expectations, despite a significant reduction in fluid secretion, neural stimulation resulted in enhanced Ca²⁺ signals with altered spatiotemporal characteristics in vivo. Muscarinic stimulation resulted in reduced activation of the Ca²⁺-activated Cl^- channel, TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca²⁺. Super-resolution microscopy revealed a disruption in the colocalization of Inositol 1,4,5-trisphosphate receptor Ca²⁺ release channels with TMEM16a, and channel activation was reduced when intracellular Ca²⁺ buffering was increased. These data indicate altered local peripheral coupling between the channels. Appropriate Ca²⁺ signaling is also pivotal for mitochondrial morphology and bioenergetics. Disrupted mitochondrial morphology and reduced oxygen consumption rate were observed in DMXAA-treated animals. In summary, early in SS disease, dysregulated Ca²⁺ signals lead to decreased fluid secretion and disrupted mitochondrial function contributing to salivary gland hypofunction.