Vertical transmission of maternal DNA through extracellular vesicles associates with altered embryo bioenergetics during the periconception period

• Published in: eLife 2023-12, Vol.12
• Main Authors: Bolumar, David, Moncayo-Arlandi, Javier, Gonzalez-Fernandez, Javier, Ochando, Ana, Moreno, Inmaculada, Monteagudo-Sanchez, Ana, Marin, Carlos, Diez, Antonio, Fabra, Paula, Checa, Miguel Angel, Espinos, Juan Jose, Gardner, David K, Simon, Carlos, Vilella, Felipe
• Format: Article
• Language: English
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.88008.4

The transmission of DNA through extracellular vesicles (EVs) represents a novel genetic material transfer mechanism that may impact genome evolution and tumorigenesis. We aimed to investigate the potential for vertical DNA transmission within maternal endometrial EVs to the pre-implantation embryo and describe any effect on embryo bioenergetics. We discovered that the human endometrium secretes all three general subtypes of EV - apoptotic bodies (ABs), microvesicles (MVs), and exosomes (EXOs) - into the human endometrial fluid (EF) within the uterine cavity. EVs become uniformly secreted into the EF during the menstrual cycle, with the proportion of different EV populations remaining constant; however, MVs contain significantly higher levels of mitochondrial (mt)DNA than ABs or EXOs. During the window of implantation, MVs contain an eleven-fold higher level of mtDNA when compared to cells-of-origin within the receptive endometrium, which possesses a lower mtDNA content and displays the upregulated expression of mitophagy-related genes. Furthermore, we demonstrate the internalization of EV-derived nuclear-encoded (n)DNA/mtDNA by trophoblast cells of murine embryos, which associates with a reduction in mitochondrial respiration and ATP production. These findings suggest that the maternal endometrium suffers a reduction in mtDNA content during the preconceptional period, that nDNA/mtDNA become packaged into secreted EVs that the embryo uptakes, and that the transfer of DNA to the embryo within EVs occurs alongside the modulation of bioenergetics during implantation.