Placental mitochondria central to gestational diabetes pathogenesis?

Gestational diabetes (GDM) affects up to ∼1 in 6 pregnancies worldwide, representing ∼18 million births each year. It causes excessively big babies and difficult deliveries. There is also a strong link with the development of type 2 diabetes in the mother in later life. A failure of the mother to produce enough insulin and/or respond to insulin and appropriately control her glucose levels during pregnancy are believed to be the main culprits for GDMpathogenesis and its associated health risks to mother and baby. However, increasing evidence suggests that the placenta and particularly the function of its mitochondria may play a role. It is well recognised that mitochondria generateATP to fuel placental development, macromolecule synthesis and substrate exchange during pregnancy. They also produce reactive oxygen species (ROS), which are important signalling molecules that control placental functions in normal and compromised gestational environments (Lu and Sferruzzi-Perri, 2021). Although less studied, mitochondria are also responsible for the synthesis of steroid hormones, like progesterone and oestrogen, which control maternal insulin production and action during gestation (Napso et al. 2018, Sferruzzi-Perri et al. 2020). Previous work has shown that mitochondrial functional capacity is aberrant in term placental tissue from women with GDM (Sobrevia et al. 2020). However, the placenta is a heterogeneous organ and to understand the aetiology of GDM and its associated health risks, it is paramount to define the cellular contribution of changes in placental mitochondrial function. The investigation by Fisher and colleagues (2021) in The Journal of Physiology aimed to address this key knowledge gap by performing analyses of mitochondrial function in the two main trophoblast lineages, the cytotrophoblast (CTB) and syncytiotrophoblast (STB) in term placenta from women with GDM (Fisher et al. 2021). The CTB is the proliferating progenitor cell of the STB, a multinucleated trophoblast layer that is specialised in hormone synthesis and materno–fetal substrate exchange. Earlier work from the research group, as well as others, had shown that CTB and STB mitochondria vary in their functional capacity (Bustamante et al. 2014, Kolahi et al. 2017, Fisher et al. 2019). In this study, Fisher and colleagues used placental tissue homogenisation and differential centrifugation to obtain pure mitochondrial isolates from the CTB and STB of placenta from women with GDM (Fisher et al. 2021). They then performed high resolution respirometry, the gold-standard technique for examining mitochondrial respiratory capacity, as well as enzymatic and protein expression assays on trophoblast mitochondrial isolates. They also performed select analyses of mitochondrial phenotype and metabolism in whole placental tissue from the same pregnancies. In doing so, they could apply a reductionist approach to provide greater understanding of cause and effect changes in placental mitochondria in the context of GDM. Like in healthy women, Fisher and colleagues found distinct differences in mitochondrial phenotype between CTB and STB in women with GDM (Fisher et al. 2021), reinforcing the importance of examining mitochondria in different trophoblast populations in the placenta. Of note, in women with GDM, the reduction in OXPHOS was most pronounced in CTB mitochondria and was coupled to diminished ATP production. Fascinatingly, the reduced rates of OXPHOS and ATP production in CTB mitochondria from GDM pregnancies were similar to those seen in STB mitochondria from normoglycaemic controls. It is interesting to speculate whether such changes may reflect metabolic suppression that is uncoupled from CTB differentiation into STB (Kolahi et al. 2017) and shed light on the reported villous immaturity seen in the placenta of women with GDM (Huynh et al. 2015). Mitochondria utilise substrates provided by the breakdown of glucose and fatty acid to generate ATP. Although substrate preference was not examined in this study, whether the overall reduction in respiratory function by CTB and STB mitochondria lead to a greater placental supply of such nutrients to the developing fetus in vivo is unknown. Moreover, combined with the finding that glucose 6-phosphatase (G6P), a rate-limiting enzyme in glucose production, is increased in placentas from these GDM women (Fisher et al. 2021), it may provide some explanation for the heavier birthweight (although non-significantly different from controls) and greater risk of increased birthweight and offspring adiposity seen in GDM pregnancies, more generally. Strategies to control ROS levels using antioxidant enzymes were also differentially altered in CTB and STB mitochondria from the placenta of women with GDM, and suggested enhanced vulnerability of CTB and increased protection of STB to ROS-mediated damage. It is interesting to hypothesise whether this increased arming of the STB in GDM pregnancy may be adaptive, since the STB is bathed in maternal blood and hence is directly exposed to the hyperglycaemia, as well as other aberrant circulating factors in women with GDM. If so, this would safeguard exchange and endocrine functions of the STB to support the fetus until delivery. Whilst oxidative stress levels in the placenta were not measured in this study, it would be great to explore whether altered trophoblast mitochondrial antioxidant capacity provides some insight into the pathways leading to elevated oxidative stress in the maternal circulation and altered insulin sensitivity in GDM pregnancies (Sobrevia et al. 2020). Enhanced progesterone synthesis was observed in CTB and STB mitochondria but not whole placental tissue from women with GDM, underscoring the merit of applying a reductionist approach to provide greater resolution in identifying defects in placental function. Enhanced progesterone production is in keeping with the notion of a placental origin for GDM pathogenesis (Napso et al. 2018, Sferruzzi-Perri et al.