Impaired Mitochondrial Biogenesis Inhibits Epithelial-Mesenchymal Transition in Villi of PCOS Patients.

Abstract

Context: Polycystic ovary syndrome (PCOS) is accompanied by impaired mitochondrial biogenesis in the ovary and uterus. Whether impaired mitochondrial biogenesis exhibits in villi of PCOS, and its effect and underlying mechanism remain unclear.

Objective: This work aimed to investigate mitochondrial biogenesis status and effect on villi of PCOS patients.

Methods: Placenta RNA-sequencing data of PCOS downloaded from the GEO database was analyzed with Gene Set Enrichment Analysis (GSEA). GSEA results were validated in first-trimester villi of 8 PCOS patients with euploid miscarriage and 22 matched controls. The function and impact of mitochondrial biogenesis on trophoblast cells were investigated using human trophoblast cell lines HTR-8/SVneo and BeWo.

Results: Mitochondria-related and epithelial-mesenchymal transition (EMT) pathways were enriched in placentas of PCOS. In villi of PCOS patients with euploid miscarriage, reduced mitochondrial DNA copy number (mtDNA CN) and N-cadherin protein level, and an elevated E-cadherin protein level were detected, indicating mitochondrial biogenesis dysfunction and impaired EMT. 5 α-Dihydrotestosterone (DHT) exposure downregulated mtDNA CN via reducing mitochondrial transcription factor A (TFAM) level, a critical transcription factor of mtDNA, in HTR-8/SVneo cells. Decreased expression level of TFAM was observed in villi of PCOS. Knockdown of TFAM significantly impeded EMT, characterized by decreased levels of N-cadherin and vimentin in HTR-8/SVneo cells, and increased level of E-cadherin in BeWo cells. Reduction of reactive oxygen species (ROS) mitigated TFAM knockdown-induced impairment of EMT via increasing nuclear Yes-associated protein level in trophoblast cells.

Conclusion: The villi of PCOS patients with euploid miscarriage exhibited impaired mitochondrial biogenesis. Androgen-induced downregulation of TFAM impeded EMT via ROS/YAP axis in trophoblast cell.