Potential therapeutic target for early-onset preeclampsia

Research by CTR in collaboration with Andrew Murray identified a protein response pathway during preeclampsia which could provide a new insight for potential therapeutic target of the disease

Preeclampsia is a major cause of maternal and neonatal mortality and can increase the risk of heart disease among mothers and offspring. Early-onset preeclampsia (PE < 34 wk), which occurs before 34 weeks of gestation, is thought to be triggered by oxidative stress tied to defective placentation, but the underlying molecular mechanisms are unclear. Hong Wa Yung et al. (pp. 18109–18118) explored the role of mitochondrial respiration in placentas from patients with PE < 34 wk. Compared with controls, PE < 34 wk placentas had a greater number of abnormal and swollen mitochondria with distorted inner-membrane folds as well as rounded, short mitochondria that suggested fragmentation. Respirometry analysis of mitochondrial function revealed that oxidative phosphorylation, the key energy-generating mechanism, was 60% lower in PE < 34 wk placentas, compared with controls; protein levels of almost all major complexes of the electron transport chain, the assemblage of energy-generating mitochondrial proteins, were largely unaltered in PE < 34 wk placentas, compared with controls. Subjecting trophoblast cells from the placenta to repeated bouts of oxygen limitation and reoxygenation mirrored the mitochondrial dysfunction observed in PE < 34 wk placentas. Additionally, mitochondrial respiration defects were tied to activation of a noncanonical stress response mechanism specific to mitochondria, called the mitochondrial unfolded protein response pathway, as well as reduced levels of the CLPP protease enzyme, implicated in the pathway. Activating the pathway or reducing CLPP levels reduced mitochondrial respiration in a placental cell line in vitro. According to the authors, the findings suggest that the mitochondrial unfolded protein response pathway may represent a therapeutic target in PE < 34 wk. — P.N.

Reference: Noncanonical mitochondrial unfolded protein response impairs placental oxidative phosphorylation in early-onset preeclampsia, Hong Wa Yung, Francesca Colleoni, Emilie Dommett, Tereza Cindrova-Davies, John Kingdom, Andrew J. Murray, and Graham J. Burton PNAS (36) 18109-18118; https://doi.org/10.1073/pnas.1907548116