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  3. Targeting trophoblast cell mitochondrial dysfunction in preeclampsia via drug repurposing

Targeting trophoblast cell mitochondrial dysfunction in preeclampsia via drug repurposing

  • Chem Biol Interact. 2026 Jan 25:424:111883. doi: 10.1016/j.cbi.2025.111883.
Dinara Afrose 1,  Sofía Alfonso-Sánchez 2,  Ashleigh Philp 3,  Philip M Hansbro 4,  Qian Peter Su 5,  Lana McClements 6
Affiliations

Affiliations

  • 1 School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, Australia.
  • 2 School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, NSW, Australia.
  • 3 Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia; School of Medicine and Health, University of New South Wales, Kensington Campus, Sydney, NSW, Australia.
  • 4 School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, Australia; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia.
  • 5 School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, NSW, Australia. Electronic address: [email protected].
  • 6 School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, Australia; Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology, Sydney, NSW, Australia. Electronic address: [email protected].
PMID: 41407245 DOI: 10.1016/j.cbi.2025.111883
Abstract

Preeclampsia is a multifactorial pregnancy disorder characterized by the new onset of hypertension and organ damage. Mitochondrial dysfunction is central to preeclampsia pathogenesis leading to placental dysfunction and oxidative stress. This study aims to elucidate the mechanisms of mitochondrial dysfunction in first-trimester trophoblast cells and to assess the therapeutic potential of aspirin, metformin, resveratrol, and a FKBPL-based peptide (AD-01) as a strategy to improve trophoblast mitochondrial health. A 2D in vitro model using the first trimester ACH-3Ps trophoblasts were developed to mimic preeclampsia-like conditions, including hypoxia-inducible factor (HIF)-1α activation (DMOG, 100 μM), mitochondrial dysfunction (Rho-6G, 1 μg/mL), or inflammation (TNF-α, 10 ng/ml). Cells were treated for 48 h with metformin (0.5 mM), resveratrol (15 μM), AD-01 (100 nM), or aspirin (0.5 mM), in the presence of DMOG, Rho-6G or TNF--α. Mitochondrial dynamics were assessed by immunofluorescence staining, the Seahorse XF Mito Stress Test, and RT-qPCR for key genes expression regulating mitochondrial fusion (mfn1), fission (dnm1l), and Autophagy (atg5, map1lc3b). Preeclampsia-mimicking stimuli significantly altered mitochondrial networks by reducing mitochondrial size (p <0.05-0.0001), increasing circularity (p < 0.05-0.0001), and decreasing mitochondrial number per cell (p < 0.0001). Metformin notably restored mitochondrial architecture under inflammatory stress, normalized mfn1 (p < 0.05) and atg5 expression (p < 0.001), and improved cellular bioenergetics. Aspirin improved mitochondrial morphology under hypoxic conditions and reduced oxygen consumption (p < 0.01). Resveratrol and AD-01 showed context-dependent protective effects, including reduced basal respiration under inflammatory stress (p < 0.0001). These findings demonstrate that hypoxia, inflammation, and mitochondrial dysfunction contribute to mitochondrial pathology in preeclampsia and highlight aspirin, metformin, resveratrol, and AD-01 as promising targeted therapies. Tailored interventions may improve mitochondrial health and pregnancy outcomes in women with preeclampsia.

Keywords

Autophagy; Mitochondrial dynamics; Mitochondrial dysfunction; Preeclampsia; Trophoblasts.

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