RT Journal Article
SR Electronic
T1 Maternal RND3/RhoE deficiency impairs placental mitochondrial function in preeclampsia by modulating the PPARγ-UCP2 cascade
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.22.164921
DO 10.1101/2020.06.22.164921
A1 Liping Huang
A1 Yanlin Ma
A1 Lu Chen
A1 Jiang Chang
A1 Mei Zhong
A1 Zhijian Wang
A1 Ying Sun
A1 Xia Chen
A1 Fei Sun
A1 Lu Xiao
A1 Jianing Chen
A1 Yingjun Lai
A1 Chuming Yan
A1 Xiaojing Yue
YR 2021
UL http://biorxiv.org/content/early/2021/07/12/2020.06.22.164921.abstract
AB Preeclampsia (PE) is a life-threatening disease of pregnant women associated with severe hypertension, proteinuria, or multi-organ injuries. Mitochondrial-mediated placental oxidative stress plays a key role in the pathogenesis of PE. However, the underlying mechanism remains to be revealed. Here, we identify Rnd3, a small Rho GTPase, regulating 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 the respiratory chain. Moreover, Rnd3 overexpression partially rescues the mitochondrial defects and oxidative stress in human PE primary trophoblasts. Rnd3 physically interacts with the peroxisome proliferators-activated receptor γ (PPARγ) and promotes the 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 PE pathogenesis.Competing Interest StatementThe authors have declared no competing interest.ACOGAmerican College of Obstetricians and GynecologistsCK7cytokeratin 7CTBcytotrophoblastDHEdihydroethidiumFBSfetal bovine serumIUGRfetal intrauterine growth restrictionLOCloss of cristaeNRF1nuclear respiratory factor 1OCRoxygen consumption ratesPEpreeclampsiaPGC1-αPPARγ coactivator 1-αPPARαperoxisome proliferator-activated receptor αPPARγperoxisome proliferators-activated receptor γPTBsprimary trophoblastsROSreactive oxygen speciesSOD1superoxide dismutase 1SOD2superoxide dismutase 2STBsyncytiotrophoblastTFAMmitochondrial transcription factor ATUNELterminal deoxynucleotidyl transferase dUTP nick end labelingUCP2mitochondrial uncoupling protein 2