Oral Presentation ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

Metabolic Reprogramming of the Placenta in Fetal Growth Restriction (144024)

Veronica B Botha 1 2 , Caitlan R Dodd 1 2 , Heather Murray 1 3 , Kirsty G Pringle 1 2 , Roger Smith 2 4 , Joshua J Fisher 2 4
  1. School of Biomedical Sciences and Pharmacy, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia , Callaghan, NSW, Australia
  2. Reproductive and Family Health Research Program, Reproductive and Family Health Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia , New Lambton Heights, NSW, Australia
  3. Precision Medicine and Health Program, , Precision Medicine and Health Program, Hunter Medical Research Institute, New Lambton Heights, University of Newcastle, Callaghan, New South Wales, Australia , New Lambton Heights, NSW, Australia
  4. Mothers and Babies Research Centre, Mothers and Babies Research Centre, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia , Callaghan, NSW, Australia

Background:

Fetal growth restriction (FGR) is a complex fetal pathology characterised by reduced fetal nutrition and oxygenation, with placental insufficiency commonly implicated. In other tissues, the presence of chronic hypoxia and nutrient scarcity switches metabolic reprogramming from oxidative phosphorylation (OXPHOS) towards aerobic glycolysis. Mitochondrial dysfunction and decreased OXPHOS is a recognised feature of the FGR placenta, however, whether the resulting energy deficit engages the canonical energy-conservation response or is instead diverted towards cellular survival remains unclear. We hypothesise that impaired OXPHOS drives a compensatory shift towards aerobic glycolysis in FGR placentae, shifting away from growth towards survival.

Methods:

Placental tissue from uncomplicated (n=20) and FGR (n=20) pregnancies (37–40 weeks) were collected. Shotgun LC-MS proteomics was performed. Unlike statistical threshold-based proteomics, the log2-fold change (FC) was used to capture the direction and magnitude of changes within specific proteins, with negative values indicating higher protein abundance and positive values indicating lower protein abundance in FGR.

Results:

In FGR placentae, mitochondrial complex I subunits, NDUFS1 and NDUFV2, were reduced (0.129 and 0.222 log2-fold, respectively), suggesting reduced OXPHOS.  This is supported by increases in proteins involved in driving aerobic glycolysis, LDHA (-0.186 log2FC) and Hexokinase 2 (-0.962 log2FC). The AMPK energy-sensing subunit PRKAG2 was reduced (0.132 log2-fold) in FGR, while mTOR (-0.206 log2-fold) and its mTORC2-defining partner RICTOR (-0.804 log2FC) were increased. This suggests a shift toward mTORC2-mediated survival signalling, an established driver of aerobic glycolysis.

Conclusion:

Together, these findings show that the FGR placenta undergoes metabolic reprogramming, upregulating glycolytic function to compensate for the reduced capacity for oxidative phosphorylation and to maintain a level of energetic homeostasis in FGR.