Hypoxia induced changes in mitochondria morphology and biogenesis in differentiating human placental cells, with a central role of PGC-1α
Introduction: There is a growing body of evidence that reduction in oxygen tension adversely influences placental development and mitochondrial function, resulting in increased susceptibility to developing pregnancy complications such as preeclampsia or growth restriction. Mitochondria exist as a dynamic network able to respond to changes in cellular oxygen levels and adapt is biogenesis as well as distribution and morphology. However, mitochondria regulation remains ill defined in the placenta, especially as it relates to the associated pregnancy complications. The aim of this study was to explore the relationship between mitochondrial alterations during hypoxia, and the molecular regulation by the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) involved in mitochondrial biogenesis.
Methods: BeWo cytotrophoblast (CT) and syncytiotrophoblast (SCT) were maintained in either 3% or 20% O2 for 72 H. Mitochondria distribution and morphology were visualized using Mitotracker staining and quantified using ImagePro; PGC-1α and PGC-1α -P(ser571) were evaluated by western blot and citrate synthase (CS) activity by spectrophotometric assay. Two-Way ANOVA, Bonferroni's comparisons test was used to examine differences among groups (n=3-6).
Results: 3% O2 induced a perinuclear accumulation of mitochondria in CT and SCT. Number of branches and mitochondrial biomass (total mitochondria area/µm2 of cell) were downregulated (2.0-fold, P<0.001) at 3% O2, as well as CS activity (5.2- and 2.7-fold, p<0.005) in CT and SCT respectively compared to 20% O2. Additionally, total PGC1α content was downregulated in CT (2.4-fold, p<0.001) and SCT (1.46-fold p=0.09) at 3% O2 and PGC1α-P(ser571) /PGC1α ratio was increased in SCT at 3% O2 (p<0.05).
Conclusion: Hypoxia altered mitochondrial distribution and morphology in placental cells, and repressed biogenesis (immunostaining and CS activity). Furthermore, our data indicate that hypoxia could decrease both PGC-1α activity and content in placenta, a hallmark of mitochondrial dysfunction. This may lead to impaired placental metabolism and contribute to the development of pregnancy complications (preeclampsia, growth restriction).