Differences in Glycolysis and Mitochondrial Respiration between Cytotrophoblast and Syncytiotrophoblast In-Vitro: Evidence for Sexual Dimorphism

Abstract

In the placenta the proliferative cytotrophoblast cells fuse into the terminally differentiated syncytiotrophoblast layer which undertakes several energy-intensive functions including nutrient uptake and transfer and hormone synthesis. We used Seahorse glycolytic and mitochondrial stress tests on trophoblast cells isolated at term from women of healthy weight to evaluate if cytotrophoblast (CT) and syncytiotrophoblast (ST) have different bioenergetic strategies, given their different functions. Whereas there are no differences in basal glycolysis, CT have significantly greater glycolytic capacity and reserve than ST. In contrast, ST have significantly higher basal, ATP-coupled and maximal mitochondrial respiration and spare capacity than CT. Consequently, under stress conditions CT can increase energy generation via its higher glycolytic capacity whereas ST can use its higher and more efficient mitochondrial respiration capacity. We have previously shown that with adverse in utero conditions of diabetes and obesity trophoblast respiration is sexually dimorphic. We found no differences in glycolytic parameters between sexes and no difference in mitochondrial respiration parameters other than increases seen upon syncytialization appear to be greater in females. There were differences in metabolic flexibility, i.e., the ability to use glucose, glutamine, or fatty acids, seen upon syncytialization between the sexes with increased flexibility in female trophoblast suggesting a better ability to adapt to changes in nutrient supply.

Influence of Neonatal Sex on Breast Milk Protein and Antioxidant Content in Spanish Women in the First Month of Lactation

“…Firstly, the placenta exhibits a sexual dimorphism; being female placenta more adaptable [ 17 , 18 ]. The better ability of female placenta to adjust to changes may also explain the worse outcomes of males in situations of insufficient blood, oxygen or nutrient supply evidenced in humans [ 19 , 20 ] and confirmed in experimental animals [ 21 ]. A meta-analysis suggests that the occurrence of major pregnancy complications is also higher in women carrying male fetuses [ 22 ].…”

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation

“…11 Finally, our metabolic data aligns with work by others that suggests syncytiotrophoblasts are more metabolically active than cytotrophoblasts. 18 Overall, this work provides evidence that mitochondrial citrate metabolism is regulated during differentiation and that differentiation is associated with decreased citrate efflux and increased forward flux through the TCA cycle. Loss of CIC results in impaired biochemical differentiation and broad changes in gene expression, though does not impair morphologic differentiation.…”

“…Prior work highlights differences in cytotrophoblast and syncytiotrophoblast metabolism using Seahorse respirometry. 17,18 Our work specifically demonstrates that differentiation is associated with increased ATP concentration and increased TCA cycle metabolite abundance and enrichment from 13 C-labeled substrate. Based on our carbon tracing studies, cytotrophoblasts efflux mitochondrial citrate to a greater extent than syncytiotrophoblasts, whereas syncytiotrophoblasts preferentially retain citrate within the TCA cycle to a greater extent.…”

“…[13][14][15][16] Recent work using high-resolution respirometers has demonstrated that cytotrophoblasts and syncytiotrophoblasts differ in their cellular metabolism. 17,18 However, differences in oxygen consumption rates from supplied substrates do not fully capture how mitochondrial routing of metabolites may alter cellular outcomes.…”

Placental Related Disorders of Pregnancy

“…Finally, a very topical and informative overview highlighting the role of the placenta and the use of low-dose aspirin in the prevention of pre-eclampsia [ 4 , 5 ]. In addition to the reviews, our collection also contains several novel studies covering pre-eclampsia [ 6 , 7 , 8 ]; fetal growth restriction [ 7 , 9 , 10 , 11 ]; calcium signaling [ 12 ]; placental oxidative stress, nutrition, senescence and apoptosis [ 6 , 9 , 13 , 14 , 15 ]; sexual dimorphism [ 16 , 17 , 18 ], intrahepatic cholestasis [ 19 ]; placental vascular modelling [ 20 ]; and placental villous explant culture models [ 21 ].…”