AMPK regulates homeostasis of invasion and viability in trophoblasts by redirecting glucose metabolism: Implications for pre-eclampsia

Xu, Ping, Zheng, Yangxi, Liao, Jiujiang, Hu, Mingyu, Yang, Yike, Zhang, Baozhen, Kilby, Mark D., Fu, Huijia, Liu, Yamin, Zhang, Fumei, Xiong, Liling, Liu, Xiyao, Jin, Huili, Wu, Yue, Huang, Jiayu, Han, Tingli, Wen, Li, Gao, Rufei, Fu, Yong, Fan, Xiujun, Qi, Hongbo, Baker, Philip N. and Tong, Chao (2023) AMPK regulates homeostasis of invasion and viability in trophoblasts by redirecting glucose metabolism: Implications for pre-eclampsia. Cell Proliferation, 56 (2). ISSN 0960-7722

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Abstract

Pre-eclampsia (PE) is deemed an ischemia-induced metabolic disorder of the placenta due to defective invasion of trophoblasts during placentation; thus, the driving role of metabolism in PE pathogenesis is largely ignored. Since trophoblasts undergo substantial glycolysis, this study aimed to investigate its function and regulatory mechanism by AMPK in PE development. Metabolomics analysis of PE placentas was performed by gas chromatography–mass spectrometry (GC–MS). Trophoblast-specific AMPKα1-deficient mouse placentas were generated to assess morphology. A mouse PE model was established by Reduced Uterine Perfusion Pressure, and placental AMPK was modulated by nanoparticle-delivered A769662. Trophoblast glucose uptake was measured by 2-NBDG and 2-deoxy-d-[3H] glucose uptake assays. Cellular metabolism was investigated by the Seahorse assay and GC–MS.PE complicated trophoblasts are associated with AMPK hyperactivation due not to energy deficiency. Thereafter, AMPK activation during placentation exacerbated PE manifestations but alleviated cell death in the placenta. AMPK activation in trophoblasts contributed to GLUT3 translocation and subsequent glucose metabolism, which were redirected into gluconeogenesis, resulting in deposition of glycogen and accumulation of phosphoenolpyruvate; the latter enhanced viability but compromised trophoblast invasion. However, ablation of AMPK in the mouse placenta resulted in decreased glycogen deposition and structural malformation. These data reveal a novel homeostasis between invasiveness and viability in trophoblasts, which is mechanistically relevant for switching between the ‘go’ and ‘grow’ cellular programs.

Item Type:	Article
Additional Information:	Data Availability Statement: Data and materials described in the manuscript will be available upon reasonable request to the corresponding authors; delivery charges and a material transfer agreement may apply. Funding information: National Natural Science Foundation of China, Grant/Award Numbers: 81671488, 81871189, 82071675, U21A20346, 82171662; Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine; National Key R&D Program of China, Grant/Award Number: 2022YFC2702400
Uncontrolled Keywords:	cell biology ,/dk/atira/pure/subjectarea/asjc/1300/1307
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	08 May 2025 08:34
Last Modified:	08 May 2025 08:34
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99208
DOI:	10.1111/cpr.13358

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