State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu , People's Republic of China.
West China-Washington Mitochondria and Metabolism Center, Department of Anesthesiology, West China Hospital, Sichuan University , Chengdu , People's Republic of China.
Am J Physiol Cell Physiol. 2018 Sep 1;315(3):C389-C397. doi: 10.1152/ajpcell.00248.2017. Epub 2018 May 16.
Oxygen deficiency is associated with various oral diseases, including chronic periodontitis, age-related alveolar bone loss, and mechanical stress-linked cell injury from orthodontic appliances. Nevertheless, our understanding of the impact of hypoxia on periodontal tissues and its biochemical mechanism is still rudimentary. The purpose of this research was to elucidate the effects of hypoxia on the apoptosis of human periodontal ligament stem cells (PDLSCs) in vitro and the underlying mechanism. Herein, we showed that cobalt chloride (CoCl) triggered cell dysfunction in human PDLSCs in a concentration-dependent manner and resulted in cell apoptosis and oxidative stress overproduction and accumulation in PDLSCs. In addition, CoCl promoted mitochondrial fission in PDLSCs. Importantly, CoCl increased the expression of dynamin-related protein 1 (Drp1), the major regulator in mitochondrial fission, in PDLSCs. Mitochondrial division inhibitor-1, pharmacological inhibition of Drp1, not only inhibited mitochondrial fission but also protected against CoCl-induced PDLSC dysfunction, as shown by increased mitochondrial membrane potential, increased ATP level, reduced reactive oxygen species (ROS) level, and decreased apoptosis. Furthermore, N-acety-l-cysteine, a pharmacological inhibitor of ROS, also abolished CoCl-induced expression of Drp1 and protected against CoCl-induced PDLSC dysfunction, as shown by restored mitochondrial membrane potential, ATP level, inhibited mitochondrial fission, and decreased apoptosis. Collectively, our data provide new insights into the role of the ROS-Drp1-dependent mitochondrial pathway in CoCl-induced apoptosis in PDLSCs, indicating that ROS and Drp1 are promising therapeutic targets for the treatment of CoCl-induced PDLSC dysfunction.
缺氧与各种口腔疾病有关，包括慢性牙周炎、与年龄相关的牙槽骨丧失以及正畸器械引起的机械应激相关细胞损伤。然而，我们对缺氧对牙周组织的影响及其生化机制的理解仍然很初步。本研究旨在阐明缺氧对体外人牙周膜干细胞（PDLSCs）凋亡的影响及其潜在机制。在此，我们表明氯化钴（CoCl）以浓度依赖的方式引发人 PDLSCs 细胞功能障碍，导致细胞凋亡和氧化应激产物在 PDLSCs 中过度产生和积累。此外，CoCl 促进 PDLSCs 中的线粒体裂变。重要的是，CoCl 增加了 PDLSCs 中线粒体裂变的主要调节因子——动力相关蛋白 1（Drp1）的表达。线粒体分裂抑制剂-1，Drp1 的药理学抑制，不仅抑制了线粒体裂变，而且还防止了 CoCl 诱导的 PDLSC 功能障碍，表现为线粒体膜电位增加、ATP 水平增加、活性氧（ROS）水平降低和凋亡减少。此外，ROS 的药理学抑制剂 N-乙酰半胱氨酸（NAC）也消除了 CoCl 诱导的 Drp1 表达，并防止了 CoCl 诱导的 PDLSC 功能障碍，表现为线粒体膜电位恢复、ATP 水平升高、线粒体分裂抑制和凋亡减少。总之，我们的数据提供了关于 ROS-Drp1 依赖性线粒体途径在 CoCl 诱导的 PDLSCs 凋亡中的作用的新见解，表明 ROS 和 Drp1 是治疗 CoCl 诱导的 PDLSC 功能障碍的有前途的治疗靶点。
