Clock Genes Regulate Ca2+ Signaling and Mitochondrial Bioenergetics to Inhibit Sjögren Disease.

OBJECTIVE

Although Ca2 + signaling and metabolism have been identified as key determinants for the development of Sjögren disease (SjD), the intricate connection between them and salivary gland physiology remains poorly understood.

METHODS

Fluorescence-based Ca2+ imaging, RNA sequencing, and mitochondrial activity were used to investigate the effects of circadian rhythm and salivary gland dysfunction. Critical findings were confirmed by studying mouse models of SjD and human salivary gland samples.

RESULTS

We identified that Ca2+ entry is essential in modulating Clock genes and circadian rhythm, which also modulate salivary gland secretion and the expression of Stim and Orai genes. Mechanistically, our data show that Bmal2 binding in the promoter region of Stim1 modulates its expression, thereby regulating Ca2+ entry and mitochondrial bioenergetics and providing cyclic rhythm-mediated regulation of cellular physiology. To assess Ca2+-dependent circadian rhythms, we used diet perturbation, in which a Ca2+-deficient diet specifically impacts the Clock gene's rhythm, which was reversed by Ca2+ supplementation. Circadian rhythm-mediated regulation of fluid secretion, as well as STIM1 genes, was also altered in an SjD mouse model. In addition, human patients with SjD also showed dysregulation of CLOCK and STIM1 genes, which could alter salivary physiology, leading to the development of the SjD phenotype.

CONCLUSION

Our results provide the first comprehensive evidence of a reciprocal relationship between circadian rhythm, Ca2+ signaling, and metabolism, which is critical for cellular physiology and disease development/progression.