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Diabetes Promotes Hyposalivation of Submandibular Gland Through PINK1/Parkin-Mediated Mitophagy
37 Pages Posted: 27 Sep 2018
More...Abstract
Type 2 diabetes mellitus is often accompanied by dysfunction of salivary glands, which leads to impaired saliva secretion. However, the molecular mechanism underlying diabetic hyposalivation remains unclear and was the purpose of this study. The molecular mechanisms that underlie diabetic hyposalivation were studied by db/db mice and SMG-C6 cells. Here, we found morphological changes and decreased stimulated salivary flow rates of submandibular gland (SMG) in diabetic mice. We observed structural damage of mitochondria and significant decrease in mitochondrial membrane potential, mtDNA copy number and ATP content in diabetic SMG. More mitophagosomes and higher expression of autophagy related proteins were detected in diabetic SMG. Increased levels of proteins PINK1 and Parkin indicating that PINK1/Parkin-mediated mitophagy was activated in diabetic SMG. Consistently, high glucose (HG) induced mitochondrial dysfunction and PINK1/Parkin-mediated mitophagy in cultured SMG-C6 cells. HG also induced increasing of ROS and reduced activation of antioxidants in SMG-C6 cells. Preincubation with NAC significantly suppressed HG-induced mitochondrial dysfunction and mitophagy. Additionally, HG decreased ERK1/2 phosphorylation and activation of ERK1/2 by LM22B-10 decreased HG-induced mitophagy, as evidenced by less autophagy related proteins expression. Taken together, 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.
Funding: This work was supported by the National Natural Science Foundation of China (grant number 81570993) and the Beijing Natural Science Foundation (grant number 7162100).
Declaration of Interest: No potential conflicts of interest relevant to this article were reported.
Ethical Approval: All experimental procedure was approved by the Ethics Committee of Animal Research, Peking University Health Science Center and complied with the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996).
Keywords: Diabetes mellitus; Hyposalivation; Submandibular gland; Mitochondrion; Mitophagy
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