Type 2 diabetes‐induced hyposalivation of the submandibular gland through PINK1/Parkin‐mediated mitophagy

Diabetes is often accompanied by dysfunction of salivary glands. However, the molecular mechanism remains unclear. The mechanisms that underlie diabetic hyposalivation were studied by db/db mice and SMG‐C6 cells. We found morphological changes and decreased stimulated salivary flow rates of the submandibular gland (SMG) in diabetic mice. We observed structural changes and dysfunction of mitochondria. More mitophagosomes and higher expression of autophagy‐related proteins were detected. Increased levels of proteins PINK1 and Parkin indicate that PINK1/Parkin‐mediated mitophagy was activated in diabetic SMG. Consistently, high glucose (HG) induced mitochondrial dysfunction and PINK1/Parkin‐mediated mitophagy in cultivated SMG‐C6 cells. HG also increased reactive oxygen species (ROS) and lessened activation of antioxidants in SMG‐C6 cells. In addition, HG lowered ERK1/2 phosphorylation and HG‐induced mitophagy was decreased after ERK1/2 was activated by LM22B‐10. Altogether, these data suggest that ROS played a crucial role in diabetes‐induced mitochondrial dysfunction and PINK1/Parkin‐mediated mitophagy and ERK1/2 was required in HG‐induced mitophagy in SMG. Diabetes leads to a characteristic hyposalivation of the submandibular gland in db/db mice, which is accompanied by increased mitochondrial dysfunction and PINK1/Parkin‐mediated mitophagy. The increased reactive oxygen species production may be responsible for modulating mitophagy in the diabetic submandibular gland. Furthermore, ERK1/2 was required for diabetes‐induced mitophagy.