Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

Abstract

Ferroptosis, a form of regulated necrotic cell death, plays roles in diverse physiological processes and diseases. Women with polycystic ovary syndrome (PCOS) have hyperandrogenism and insulin resistance (HAIR) and an increased risk of miscarriage and placental dysfunction during pregnancy. However, whether maternal HAIR alters mechanisms leading to ferroptosis in the gravid uterus and placenta remains unknown. Previous studies in rats showed that maternal exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) from gestational day 7.5 to 13.5 induces HAIR and subsequently leads to placental insufficiency and fetal loss. We therefore hypothesized that maternal HAIR triggers ferroptosis in the uterus and placenta in association with fetal loss in pregnant rats. Compared with controls, we found that co-exposure to DHT and INS led to decreased levels of Gpx4 and glutathione (GSH), increased GSH+glutathione disulfide (GSSG) and malondialdehyde (MDA), aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition, and activated ERK/p38/JNK phosphorylation in the gravid uterus. However, in the placenta, DHT and INS exposure only partially altered the expression of ferroptosis-related markers (e.g., region-dependent Gpx4, GSH+GSSG, MDA, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). In the uteri co-exposed to DHT and INS, we also observed shrunken mitochondria with electron-dense cristae, which are key features of ferroptosis-related mitochondrial morphology, as well as increased expression of Dpp4, a mitochondria-encoded gene responsible for ferroptosis induction. In contrast, in placentas co-exposed to DHT and INS we found decreased expression of Dpp4 mRNA and increased expression of Cisd1 mRNA (a mitochondria-encoded iron-export factor). Further, DHT+INS-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal HAIR causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Furthermore, our data suggest other cell death pathways may play a role in coordinating or compensating for HAIR-induced ferroptosis when the gravid uterus and placenta are dysfunctional.

Ferritinophagy and ferroptosis in the management of metabolic diseases

“…Moreover, Zhang and colleagues reported that maternal HAIR activates ferroptosis in the placenta and gravid uterus through distinct mechanisms. Also, they showed that other cell death mechanisms may be involved in the coordination or compensation of HAIR-induced ferroptosis in the dysfunctional placenta and gravid uterus [45].…”

Protective and multi-organ effects of MOTS-c and other mitochondrial-derived peptides in the endocrine system

“…MOTS-c treatment of GDM mice was also associated with re-duced blood glucose levels and reduced offspring mortality compared to GDM controls without administered MOTS-c [43]. It is worth noting that administration of insulin in adult female Sprague-Dawley rats leads to a significant decrease in MOTS-c protein levels in both uterine and placental tissues [44,45]. Moreover, lipid infusion significantly increases plasma MOTS-c in healthy women and patients with polycystic ovary syndrome (PCOS); however, insulin administration suppresses lipid-induced increase of MOTS-c protein levels in plasma [46].…”