Mitochondrial malfunction mediates impaired cholinergic Ca²⁺ signalling and submandibular salivary gland dysfunction...

Xerostomia (dry-mouth syndrome) is a painful and debilitating condition that frequently occurs in individuals with diabetes and is associated with impaired saliva production and salivary gland hypofunction. Saliva fluid production relies on Ca²⁺-coupled secretion driven by neurotransmitter stimulation of submandibular acinar cells. Although impairments in intracellular Ca²⁺ signalling have been reported in various xerostomia models, the specific Ca²⁺-dependent mechanisms underlying saliva fluid hypofunction in diabetes remain unclear. In this study, we show that diabetic animals exhibit severe xerostomia, evident by reduced saliva flow rate, diminished total protein content, and decreased amylase activity in the saliva secreted by submandibular glands. These impairments remained resistant to exogenous cholinergic stimulation. In submandibular acinar cells, the intracellular Ca²⁺ signals evoked by cholinergic stimulation were reduced and delayed in diabetes, caused by malfunctioning mitochondria. Upon initiation of cholinergic-evoked Ca²⁺ signals, mitochondria accumulate higher Ca²⁺ and fail to redistribute Ca²⁺ influx and facilitate the store-operated Ca²⁺ entry effectively. Structural damage to mitochondria was evident in the acinar cells in diabetes. These findings provide insights into the potential targeting of malfunctioning mitochondria for the treatment of diabetic xerostomia as an alternative strategy to the existing pharmacotherapeutic approaches. This article is part of the Special Issue on "Ukrainian Neuroscience".