Dysregulated Ca 2+ signaling, fluid secretion, and mitochondrial function in a mouse model of early Sjögren's syndrome.

Saliva is essential for oral health. The molecular mechanisms leading to physiological fluid secretion are established, but factors that underlie secretory hypofunction, specifically related to the autoimmune disease Sjögren's syndrome (SS) are not fully understood. SS-like disease was induced by the treatment with 5,6-Dimethyl-9-oxo-9H-xanthene-4-acetic acid (DMXAA), an activator of the stimulator of the interferon gene (STING) pathway. This mouse model mimics exposure to foreign cytoplasmic ribonucleotides occurring following viral and bacterial infection and thought to be an initiating event in SS. Neurotransmitter-stimulated increases in cytoplasmic [Ca 2+ ] are central to stimulating fluid secretion, primarily by increasing the activity of the Ca 2+ -activated Cl - channel, TMEM16a. Paradoxically, in DMXAA-treated mice in vivo imaging demonstrated that neural-stimulation resulted in greatly enhanced Ca 2+ levels when a significant reduction in fluid secretion was observed. Notably, in the disease model, the spatiotemporal characteristics of the Ca 2+ signals were altered to result in global rather than largely apically confined Ca 2+ rises observed physiologically. Notwithstanding the augmented Ca 2+ signals, muscarinic stimulation resulted in reduced activation of TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca 2+ . However, super-resolution microscopy revealed a disruption in the localization of Inositol 1,4,5-trisphosphate receptor Ca 2+ release channels in relation to TMEM16a. Appropriate Ca 2+ signaling is also pivotal for mitochondrial morphology and bioenergetics and secretion is an energetically expensive process. Disrupted mitochondrial morphology, a depolarized mitochondrial membrane potential, and reduced oxygen consumption rate were observed in DMXAA-treated animals compared to control animals. We report that early in SS disease, dysregulated Ca 2+ signals lead to decreased fluid secretion and disrupted mitochondrial function contributing to salivary gland hypofunction and likely the progression of SS disease.