Objectives
The ability of a tissue to sense and response to oxygen is linked to the metabolic and mitochondrial signalling within. This phenomenon has been deemed mitochondrial oxygen sensing. Oxygen sensing has been well characterised in arterial chemoreceptors and the carotid body to be dependent on mitochondrial subunit composition. However, the role of mitochondria in the response to varying oxygen level in the placenta remains unclear. A mechanism that is of particular important to understanding gestational complications such as fetal growth restriction (FGR), where poor perfusion and hypoxia are common. This study aimed to determine if mitochondrial oxygen sensing mechanisms and subunit composition plays a role in the development of FGR through the inability of the placenta to respond to varying oxygen levels in-utero.
Methods
Fetal growth restricted placentae (n=8) and gestational matched healthy term control (n=14) pregnancies were utilised. Metabolic and hypoxic signalling was assessed at a transcriptional and translational level via PCR and Immunoblotting. Functional mitochondrial characteristics were measured by Seahorse XF.
Results
Hypoxic (ARNT, HIF1a,) and mitochondrial subunit genes (NDUFS2, COX4I1, COX4I2) were higher (p=<0.05) in FGR compared to term control. A finding not conserved at the protein level for mitochondrial subunit NDUSF2 (p=<0.0001). Likewise, metabolic regulator AMPK decreased (p=<0.05) in FGR tissue along with a functional decline in oxidative phosphorylation (p=<0.03) that was not explained by a change in mitochondrial content.
Conclusion
This data demonstrates the potential for mitochondrial subunits to alter the hypoxic response in the placenta in a manner akin to oxygen sensing in other tissues. Notably, FGR placenta saw a functional decline in mitochondrial oxidative phosphorylation when compared to healthy term placentae, a key indicator of mitochondrial dysfunction. Given the importance of mitochondria to oxygen sensing and response to hypoxia these finding may provide a novel mechanism which underpins the pathogenesis of FGR.