Noncanonical mitochondrial unfolded protein response impairs placental oxidative phosphorylation in early-onset preeclampsia.

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dc.creatorYung, Hong Wa
dc.creatorColleoni, Francesca
dc.creatorDommett, Emilie
dc.creatorCindrova-Davies, Tereza
dc.creatorKingdom, John
dc.creatorMurray, Andrew J
dc.creatorBurton, Graham J
dc.date2019-07-31T23:30:10Z
dc.date2019-07-31T23:30:10Z
dc.date2019-09-03
dc.date.accessioned2026-08-03T04:18:15Z
dc.descriptionPreeclampsia (PE) is a dangerous complication of pregnancy, especially when it presents at <34 wk of gestation (PE < 34 wk). It is a major cause of maternal and fetal morbidity and mortality and also increases the risk of cardiometabolic diseases in later life for both mother and offspring. Placental oxidative stress induced by defective placentation sits at the epicenter of the pathophysiology. The placenta is susceptible to activation of the unfolded protein response (UPR), and we hypothesized this may affect mitochondrial function. We first examined mitochondrial respiration before investigating evidence of mitochondrial UPR (UPRmt) in placentas of PE < 34 wk patients. Reduced placental oxidative phosphorylation (OXPHOS) capacity measured in situ was observed despite no change in protein or mRNA levels of electron transport chain complexes. These results were fully recapitulated by subjecting trophoblast cells to repetitive hypoxia-reoxygenation and were associated with activation of a noncanonical UPRmt pathway; the quality-control protease CLPP, central to UPRmt signal transduction, was reduced, while the cochaperone, TID1, was increased. Transcriptional factor ATF5, which regulates expression of key UPRmt genes including HSP60 and GRP75, showed no nuclear translocation. Induction of the UPRmt with methacycline reduced OXPHOS capacity, while silencing CLPP was sufficient to reduce OXPHOS capacity, membrane potential, and promoted mitochondrial fission. CLPP was negatively regulated by the PERK-eIF2α arm of the endoplasmic reticulum UPR pathway, independent of ATF4. Similar changes in the UPRmt pathway were observed in placentas from PE < 34 wk patients. Our results identify UPRmt as a therapeutic target for restoration of placental function in early-onset preeclampsia.
dc.formatPrint-Electronic
dc.formatapplication/pdf
dc.identifier0027-8424
dc.identifierhttps://www.repository.cam.ac.uk/handle/1810/295134
dc.identifier10.17863/CAM.42204
dc.identifier1091-6490
dc.identifier.urihttps://repo.dare.co.zw/handle/123456789/187570
dc.languageeng
dc.languageeng
dc.publisherProceedings of the National Academy of Sciences
dc.publisherhttps://doi.org/10.1073/pnas.1907548116
dc.rightsAll rights reserved
dc.subjectmitochondria
dc.subjectpreeclampsia
dc.subjectunfolded protein response
dc.subjectActivating Transcription Factors
dc.subjectChaperonin 60
dc.subjectEukaryotic Initiation Factor-2
dc.subjectFemale
dc.subjectHSP70 Heat-Shock Proteins
dc.subjectHumans
dc.subjectMitochondria
dc.subjectMitochondrial Proteins
dc.subjectOxidative Phosphorylation
dc.subjectPre-Eclampsia
dc.subjectPregnancy
dc.subjectTrophoblasts
dc.subjectUnfolded Protein Response
dc.subjecteIF-2 Kinase
dc.titleNoncanonical mitochondrial unfolded protein response impairs placental oxidative phosphorylation in early-onset preeclampsia.
dc.typeArticle

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