Work

Metformin promotes placental adaptation to hypoxic stress through mitochondrial and translational pathways

Year: 2026

Type: article

Abstract: Preeclampsia is a leading cause of maternal and perinatal morbidity worldwide, with no approved disease-modifying medical therapy. The disorder originates from placental insufficiency characterised by chronic hypoxia, oxidative stress, inflammation, and mitochondrial dysfunction within placental trophoblasts. Although metformin is widely used in pregnancy and has shown benefit in preeclampsia clinical trials, its mechanism of action including direct effects on placental protein synthesis and mitochondrial adaptation under hypoxic conditions remain poorly defined. Our aim was to determine how metformin modulates placental protein synthesis and mitochondrial function under physiological and hypoxic conditions relevant to placental dysfunction. Primary human placental trophoblasts were cultured under normoxic (8% O₂) or hypoxic (1% O₂) conditions and treated with metformin. Label-free quantitative proteomics was used to identify altered molecular pathways. Mitochondrial adaptation was assessed by analysis of mitochondrial dynamics markers, electron transport chain (ETC) complex expression, and reactive oxygen species (ROS) production. Metformin upregulated proteins involved in RNA processing, protein synthesis, and metabolism, while downregulating proteins associated with extracellular matrix organization and apoptosis. Under hypoxic conditions, metformin increased markers of mitochondrial fission and significantly upregulated ETC complexes I, II, and IV. These changes were associated with reduced cellular ROS levels. Importantly, enhanced protein synthesis occurred without activation of unfolded protein response pathways, indicating preservation of cellular homeostasis. Metformin enhances placental adaptation to hypoxic stress by coordinating protein synthesis and mitochondrial respiratory function while reducing oxidative stress. These mechanistic findings provide translational insight into how metformin may improve placental resilience and support its further evaluation as a therapeutic strategy for preeclampsia and other pregnancy complications driven by placental dysfunction. Not applicable. This study does not meet the NHMRC definition of a clinical trial.

Source: Journal of Translational Medicine

DOI: 10.1186/s12967-026-08798-4

Authors: Elif Kadife, Alesia Harper, Ishara Atukorala, Sarah Ellis, Fiona C. Brownfoot

Institutions: The University of Melbourne, Mercy Hospital for Women, La Trobe University, Australian Cancer Research Foundation, Olivia Newton-John Cancer Wellness & Research Centre

Language: English

Topic: Pregnancy and preeclampsia studies

Subfield: Obstetrics and Gynecology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,890