Department of Obstetrics, Shenzhen Maternity & Child Healthcare Hospital, the First School of Clinical Medicine, Southern Medical University, Shenzhen, Guangdong, China.
Department of Emergency, Shenzhen Children's Hospital, Shenzhen, Guangdong, China.
Bioengineered. 2022 Feb;13(2):3620-3633. doi: 10.1080/21655979.2021.1997132.
Preeclampsia (PE) is a pregnancy disorder characterized by excessive trophoblast cell death. This study aims to explore the exact mechanism of the ubiquitination level of FUN14 domain containing 1 (FUNDC1) in mitophagy and injury in hypoxic trophoblast cells. In this study, HTR-8/SVneo trophoblast cells were cultured under normoxic and hypoxic conditions and PE mouse model was established. We found low ubiquitination level of FUNDC1 in hypoxic trophoblast cells and placenta of pregnant women with PE. Proteasome inhibitor MG-132 and protease activator MF-094 were added into HTR-8/SVneo trophoblast cells. Proteasome inhibitor MG-132 decreased FUNDC1 ubiquitination level while protease activator MF-094 increased FUNDC1 ubiquitination level. Inhibition of FUNDC1 ubiquitination promoted mitophagy and mitochondrial membrane potential (Δψm) in normoxic trophoblast cells, increased levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and decreased levels of glutathione (GSH) and superoxide dismutase (SOD). In addition, FUNDC1 ubiquitination alleviated cell injury in PE mice . In conclusion, increased FUNDC1 ubiquitination level inhibited mitophagy and Δψm changes in hypoxic trophoblast cells, and thus alleviated oxidative injury.
子痫前期（PE）是一种妊娠疾病，其特征是滋养细胞过度死亡。本研究旨在探讨 FUN14 结构域包含 1（FUNDC1）泛素化水平在缺氧滋养细胞自噬和损伤中的确切机制。本研究在常氧和缺氧条件下培养 HTR-8/SVneo 滋养细胞，并建立 PE 小鼠模型。我们发现缺氧滋养细胞和 PE 孕妇胎盘 FUNDC1 的泛素化水平较低。向 HTR-8/SVneo 滋养细胞中添加蛋白酶体抑制剂 MG-132 和蛋白酶激活剂 MF-094。蛋白酶体抑制剂 MG-132 降低 FUNDC1 泛素化水平，而蛋白酶激活剂 MF-094 增加 FUNDC1 泛素化水平。抑制 FUNDC1 泛素化促进常氧滋养细胞的自噬和线粒体膜电位（Δψm），增加活性氧（ROS）和丙二醛（MDA）水平，降低谷胱甘肽（GSH）和超氧化物歧化酶（SOD）水平。此外，FUNDC1 泛素化减轻了 PE 小鼠的细胞损伤。总之，增加的 FUNDC1 泛素化水平抑制了缺氧滋养细胞的自噬和 Δψm 变化，从而减轻了氧化损伤。
