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

Abstract

Preeclampsia (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.

Placental genomic risk scores and early neurodevelopmental outcomes

“…Given the partial genetic overlap of schizophrenia with some of these disorders ( 12 , 33 ), these results suggest that the genes that uniquely map to the schizophrenia-risk loci are selectively relevant for placenta biology. Indeed, the PlacGRS genes that uniquely map to the schizophrenia-risk loci are enriched for pathways and functions associated with cellular metabolic stress, including mitochondrial dysfunction, unfolded protein response, and endoplasmic reticulum stress response, which are highly relevant for trophoblast invasion, placenta development, and pathophysiology ( 34 – 36 ) ( Fig. 4 B , SI Appendix , Results , Biological Insights about the Schizophrenia Specific Placental Risk Genes , and Datasets S1 and S2 ), in addition to brain function.…”

Unfolded Protein Response in Lung Health and Disease

“…It was recently reported that the noncanonical mitochondrial UPR impairs placental oxidative phosphorylation in early-onset preeclampsia. Thus, understanding mitochondrial stress may provide new insights regarding that pathology ( 62 ). The beneficial activities of GHRH antagonists in breast and prostate experimental models of disease have been associated with the induction of UPR and P53 ( 50 , 55 ).…”

Role of dyslipidemia in the development of early-onset preeclampsia

“…This type of PE is called early-onset PE since the gestational age of all recruited preeclamptic women started after 20 and before 34 weeks of gestation. [ 15 ]…”