Placental mitochondrial metabolic adaptation maintains cellular energy balance in pregnancy complicated by gestational hypoxia

作者：Wen Tong, Beth J. Allison, Kirsty L. Brain, Olga Patey, Youguo Niu, Kimberley J. Botting, Sage G. Ford, Tessa A. C. Garrud, Peter F. P. Wooding, Qiang Lyu, Zhang Li, Jin Ma, Alice P. Sowton, Katie A. O’Brien, Tereza Cindrová‐Davies, Hong Wa Yung, Graham J. Burton, Andrew J. Murray, Dino A. Giussani · 发表于：The Journal of Physiology · 年份：2025 · DOI：10.1113/jp287897 · 被引用次数：8 · 研究领域：Birth, Development, and Health、Pregnancy and preeclampsia studies、Mitochondrial Function and Pathology

The mechanisms that drive placental dysfunction in pregnancies complicated by hypoxia and fetal growth restriction remain poorly understood. Changes to mitochondrial respiration contribute to cellular dysfunction in conditions of hypoxia and have been implicated in the pathoaetiology of pregnancy complications, such as pre-eclampsia. We used bespoke isobaric hypoxic chambers and a combination of functional, molecular and imaging techniques to study cellular metabolism and mitochondrial dynamics in sheep undergoing hypoxic pregnancy. We show that hypoxic pregnancy in sheep triggers a shift in capacity away from β-oxidation and complex I-mediated respiration, while maintaining total oxidative phosphorylation capacity. There are also complex-specific changes to electron transport chain composition and a switch in mitochondrial dynamics towards fission. Hypoxic placentas show increased activation of the non-canonical mitochondrial unfolded protein response pathway and enhanced insulin like growth factor 2 signalling. Combined, therefore, the data show that the hypoxic placenta undergoes significant metabolic and morphological adaptations to maintain cellular energy balance. Chronic hypoxia during pregnancy in sheep activated placental mitochondrial stress pathways, leading to alterations in mitochondrial respiration, mitochondrial energy metabolism and mitochondrial dynamics, as seen in the placenta of women with pre-eclampsia. KEY POINTS: Hypoxia shifts mitochondrial respiration...