Preeclampsia (PE) is a life-threatening disease of the pregnant women, and has a profound influence on fetal development. Mitochondrial-mediated placental oxidative stress plays key role in the etiology of PE. However, the underlying mechanism remains to be revealed. Here, we identify Rnd3, a small Rho GTPase, participating in the regulation of placental mitochondrial reactive oxygen species (ROS). We showed that Rnd3 is down-regulated in primary trophoblasts isolated from PE patients. Loss of Rnd3 in trophoblasts resulted in excessive ROS generation, cell apoptosis, mitochondrial injury and proton leakage from respiratory chain. Moreover, Rnd3 overexpression partially rescues the mitochondrial defects and oxidative stress in human PE primary trophoblasts. Mechanistically, Rnd3 physically interacts with the peroxisome proliferators-activated receptor γ (PPARγ) and promotes PPARγ-mitochondrial uncoupling protein 2 (UCP2) cascade. Forced expression of PPARγ rescues deficiency of Rnd3-mediated mitochondrial dysfunction. We conclude that Rnd3 acts as a novel protective factor in placental mitochondria through PPARγ-UCP2 signaling and highlight that downregulation of Rnd3 is a potential factor involved in the pathogenesis of PE.

中文翻译：

---

母体RND3/RhoE缺乏通过调节PPARγ-UCP2级联来损害先兆子痫的胎盘线粒体功能

先兆子痫（PE）是一种危及孕妇生命的疾病，对胎儿的发育有着深远的影响。线粒体介导的胎盘氧化应激在 PE 的病因学中起关键作用。然而，潜在的机制仍有待揭示。在这里，我们确定了 Rnd3，一种小的 Rho GTPase，参与胎盘线粒体活性氧 (ROS) 的调节。我们发现 Rnd3 在从 PE 患者分离的原代滋养细胞中下调。滋养层细胞中 Rnd3 的缺失导致过量的 ROS 产生、细胞凋亡、线粒体损伤和呼吸链质子泄漏。此外，Rnd3 过表达部分挽救了人类 PE 原代滋养细胞的线粒体缺陷和氧化应激。从机制上讲，Rnd3 与过氧化物酶体增殖物激活受体 γ (PPARγ) 发生物理相互作用并促进 PPARγ-线粒体解偶联蛋白 2 (UCP2) 级联反应。PPARγ 的强制表达可挽救 Rnd3 介导的线粒体功能障碍的缺陷。我们得出结论，Rnd3 通过 PPARγ-UCP2 信号传导在胎盘线粒体中充当新的保护因子，并强调 Rnd3 的下调是参与 PE 发病机制的潜在因素。