Center for Salivary Gland Diseases of Peking University School and Hospital of Stomatology, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing, China.
Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China.
J Cell Physiol. 2020 Jan;235(1):232-244. doi: 10.1002/jcp.28962. Epub 2019 Jun 12.
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.
糖尿病常伴有唾液腺功能障碍。然而，其分子机制尚不清楚。本研究通过 db/db 小鼠和 SMG-C6 细胞研究了糖尿病低渗唾液的发生机制。我们发现糖尿病小鼠下颌下腺（SMG）发生形态学改变，刺激唾液流量减少。我们观察到了线粒体的结构改变和功能障碍。检测到更多的自噬体和更高水平的自噬相关蛋白。PINK1 和 Parkin 蛋白水平升高表明糖尿病 SMG 中 PINK1/Parkin 介导的自噬被激活。同样，高葡萄糖（HG）诱导培养的 SMG-C6 细胞中线粒体功能障碍和 PINK1/Parkin 介导的自噬。HG 还增加了活性氧（ROS），减少了 SMG-C6 细胞中抗氧化剂的激活。此外，HG 降低了 ERK1/2 磷酸化，而 ERK1/2 被 LM22B-10 激活后，HG 诱导的自噬减少。总之，这些数据表明 ROS 在糖尿病诱导的线粒体功能障碍和 PINK1/Parkin 介导的自噬中起关键作用，而 ERK1/2 是 HG 诱导的 SMG 自噬所必需的。
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