PlacentAging: The release of mtDNA in extracellular vesicles by trophoblast cells

• Applicant: Jose Martin Murrieta Coxca, Ph.D.
• Subject Area: Reproductive Medicine, Urology ; Gynaecology and Obstetrics
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545960042

The concept of PlacentAging refers to the aging process of the placenta during pregnancy. The placenta is a temporary organ that has a vital role in supporting the growth and development of the fetus. It undergoes changes and its function may be influenced by various factors including aging which is a condition associated with the progressive loss of tissue function over the lifetime and with an increased risk of age-associated pathologies. Although aging is conceived as a normal process in placenta development, advanced maternal age (AMA) may affect the aging process of the placenta. AMA is defined as being 35 years or older at the time of delivery and is associated with higher risks of pregnancy disorders and adverse perinatal outcomes. Therefore, premature placenta aging and abnormal placenta development may result in fertility complications. Although aging is a consequence of the interaction between environmental and genetic factors, other hallmarks play an important role. Among those elements, circulating cell-free mitochondrial DNA (ccf-mtDNA) is getting attention as critical in the regulation of senescence features in aging. It can be found in two conditions, membrane-bound and -unbound. The membrane-bound mtDNA is released encapsulated into cell-derived extracellular vesicles (EVs). This specific component, the release of mtDNA in EVs by trophoblast cells focuses on a molecular aspect of the placenta aging process. EVs harboring mtDNA could have implications for cellular communication and signaling within the placenta and it may be related to the overall aging and functional changes observed in the placenta during the course of pregnancy. Therefore, we hypothesize that in the context of aging, EVs derived from trophoblast cells of mothers of advanced maternal age exhibit elevated levels of membrane-bound mtDNA compared to those from younger mothers. This potential increase in membrane-bound mtDNA may contribute to the acceleration of senescence processes within the placenta. The compromised function of trophoblast cells is anticipated to manifest through diminished cell fusion, particularly in terms of trophoblast syncytialization, thereby indicating inadequate placental development associated with premature aging. Our research initiative will commence with a comprehensive analysis of mtDNA content within EVs released by primary trophoblast cells obtained from both young and AMA mothers, aiming to elucidate the molecular dynamics underlying placenta aging. Our further research in this area aims to understand molecular mechanisms involved in aging of the placenta and their impact on placental ad fetal health. This project will provide preliminary data for a full proposal on aging-associated mitochondrial dysfunction and its effects on placenta development.

• DFG Programme: Research Grants