Placental iron utilisation in fetal growth restriction: alterations in mitochondrial haem synthesis and iron-sulphur cluster assembly pathways

Abstract

Fetal growth restriction (FGR) affects ∼10% of pregnancies worldwide and is often associated with placental insufficiency. Iron is essential for maternal haematopoietic adaptations and placental processes such as mitochondrial iron-sulphur (Fe-S) cluster assembly, haem synthesis and erythropoiesis. This study aimed to characterise iron transport and downstream utilisation in FGR. Placental tissues from term uncomplicated (n = 19) and FGR (n = 18) pregnancies were analysed. Maternal iron status was retrospectively assessed from clinical records. Placental mRNA and protein expression of iron-dependent pathways were analysed via RT-qPCR, LC-MS and western blotting. Placental iron content was assessed histologically, and haem levels were measured by an activity assay. FGR pregnancies showed significantly elevated maternal serum ferritin and lower red cell distribution width, although these remained within normal clinical values. Placental iron uptake transporters TFRC and DMT1 were significantly upregulated, while the iron exporter to the fetus, ferroportin, was reduced, indicating increased iron retention in the FGR placenta. Despite altered transporter expression, Fe^{3 +} iron levels were unchanged, suggesting iron utilisation over storage. Subsequent investigations identified reduced mitochondrial Fe-S synthesis components (FDXR, FDX2, NDUFAB1, HSPA9), and a prioritisation of mitochondrial and cytosolic haem synthesis enzymes in FGR. Protein levels of haemoglobin subunits (HBG1, HBG2, HBB, HBA1) and erythrocyte membrane markers (EPB41, EPB42, SPTA1, SPTB, ANK1) were decreased. These findings reveal a compensatory response in FGR placentae, with increased iron uptake and utilisation favouring haem synthesis over Fe-S cluster formation, possibly to support oxygen handling under poor placental vascularisation and reduced fetal oxygenation, with potential consequences for mitochondrial energy metabolism. KEY POINTS: Iron plays a critical role in placental function, and while iron-dependent pathway components are well-characterised, their integrated response and adaptive reprogramming in fetal growth restriction (FGR) remain poorly understood. In FGR, maternal iron status was unchanged, however, placental iron uptake proteins were increased and ferroportin reduced, suggesting that the placenta retains iron. FGR placentae showed altered de novo mitochondrial iron-sulphur cluster (Fe-S) formation and a bottleneck in late-stage Fe-S cluster assembly. This shift in Fe-S synthesis prioritises mitochondrial and cytosolic haem synthesis pathways, consistent with increased haem utilisation and breakdown. Globin subunits were lower in protein abundance and impaired placental erythrocyte structure in FGR. Dysregulation of erythrocyte membrane proteins in FGR placentae suggests altered erythrocyte structure, potentially representing an adaptive response to inadequate vascularisation, attempting to optimise oxygen delivery to the fetus.

Keywords: erythrocyte structure; fetal growth restriction; haem synthesis; iron transport; iron–sulphur clusters; mitochondria; placenta.