Poster Presentation ESA-SRB 2023 in conjunction with ENSA

The Role of Mitochondrial Complex I in Placental Development and Fetal Growth Restriction (#396)

Siddharth Acharya 1 2 , Veronica B Botha 1 3 , John E Schjenken 2 4 , Roger Smith 1 5 , Joshua J Fisher 1 5
  1. Mothers and Babies Research Program, Hunter Medical Research Institute, Newcastle, NSW, Australia
  2. School of Environmental and Life Sciences, The University of Newcastle, Newcastle, NSW, Australia
  3. School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, NSW, Australia
  4. Infertility and Reproduction Research Program, Hunter Medical Research Institute, Newcastle, NSW, Australia
  5. School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, Australia

Aims
Fetal growth restriction (FGR) is a pregnancy complication where the fetus fails to reach its pre-determined genetic potential, impacting the health trajectory for the lifespan of the fetus by programming lifelong disorders (1). One suggested mechanism behind FGR is placental insufficiency, underpinned by mitochondrial dysfunction within the placenta. Mitochondrial respiratory complex I (NADH dehydrogenase), is the first and largest protein complex of the electron transport chain, with a critical role in ATP synthesis. Dysregulation of complex I proteins alters the efficiency of the electron transport chain, resulting in bioenergetic insufficiencies (2). Such dysregulation may alter placental implantation, invasion, and vascularisation (3). We aimed to characterise the expression of complex I proteins between healthy and FGR placentas, to assess mitochondrial functionality in placental development.
Methods
Placentas from healthy full term (n=7) and FGR pregnancies (n=7) were sampled and prepared for PCR, western blotting, and immunohistochemistry, to characterise the expression of NADH ubiquinone oxidoreductase subunit S6 (NDUFS6), subunit S2 (NDUFS2), and subunit A6 (NDUFA6).
Results
Using PCR, we identified a significantly lower mRNA expression of NDUFA6 (p < .001) in FGR placentas compared with healthy placentas, a finding consistent with whole tissue western blotting data (p = .0233). We also identified a significantly lower expression of NDUFS6 (p = .0499) in FGR placentas. In healthy term placentas NDUFS6 expression was lower in mitochondria from syncytiotrophoblasts compared with cytotrophoblasts (p < .05), consistent with immunohistochemistry results (p < .0001). Western blotting demonstrated a significantly lower expression of NDUFS2 (p = .0016) in syncytiotrophoblast mitochondria compared with cytotrophoblast mitochondria.
Conclusion
Our findings elucidate a promising novel mechanism underpinning FGR pathology, whereby mitochondrial complex I dysfunction driven by subunit dysregulation may alter ATP synthesis, causing placental insufficiency. Further investigations will facilitate the development of diagnostics and therapeutics that can promote fetal health by supporting bioenergetics and metabolism.

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  2. Sharma LK, Lu J, Bai Y. Mitochondrial respiratory complex I: structure, function and implication in human diseases. Curr Med Chem. 2009;16(10):1266-77. doi: 10.2174/092986709787846578. PMID: 19355884; PMCID: PMC4706149.
  3. Fisher JJ, Vanderpeet CL, Bartho LA, McKeating DR, Cuffe JSM, Holland OJ, Perkins AV. Mitochondrial dysfunction in placental trophoblast cells experiencing gestational diabetes mellitus. J Physiol. 2021 Feb;599(4):1291-1305. doi: 10.1113/JP280593. Epub 2020 Nov 15. PMID: 33135816.