(29) WWTR1 Controls Human Extravillous Trophoblast Development by Governing Mitochondrial Integrity and Function

Namrata Roy, Rajnish Kumar, Purbasa Dasgupta, Soma Ray, Asef Jawad Niloy, Heather Wilkins and Soumen Paul. University of Kansas Medical Center; Department of Pathology and Laboratory Medicine; Department of Biochemistry and Molecular Biology; Institute for Reproductive and Developmental Sciences. Kansas City, KS.

Abstract Text:

Your study delves into a fascinating and complex area of cellular differentiation, emphasizing the pivotal role of WWTR1 in regulating mitochondrial energetics during EVT differentiation. The connection between mitochondrial function and oxidative stress during this process is compelling, especially given the essential nature of mitochondrial oxidative phosphorylation for supporting increased energy demands during cellular differentiation. Our key findings include mitochondrial structure changes during EVT development highlighting how these alterations may be integral in meeting the energetic needs of differentiating cells. It suggests that dynamic mitochondrial morphology could be a critical factor for proper EVT maturation. By inhibiting ATP synthase with oligomycin, we provide strong evidence that mitochondrial energy production is essential for EVT differentiation. This emphasizes the necessity of functional electron transport and oxidative phosphorylation for successful differentiation, aligning with the idea that mitochondrial energy metabolism underpins cellular identity transitions. Our bulk RNA sequencing and single-cell RNA sequencing data guided us to track the suppression of mitochondrial gene expression upon WWTR1 knockdown. This finding not only supports the idea that WWTR1 plays a central role in regulating mitochondrial function but also opens the door to understanding the gene regulatory networks that control energy balance during EVT maturation. The identification of the TEAD1-WWTR1-IFI27 axis as a regulatory mechanism is particularly intriguing. It suggests a coordinated, stage-specific regulatory mechanism that could be essential for maintaining the mitochondrial environment conducive to proper EVT development. Understanding mitochondrial energetics and how WWTR1 interacts with other pathways in EVT differentiation has the potential to influence our understanding of placental diseases, such as preeclampsia, IUGR (intrauterine growth restriction), and other placental pathologies where mitochondrial dysfunction might play a role.