Abstract
Obesity in women not only impacts health and fertility but also increases the risk of metabolic disorders and obesity in the next generation(s). We
showed that oocyte mitochondrial (MT) dysfunctions play a central role in the pathogenesis of reduced oocyte quality and in the long-term impact on
offspring health. All mitochondria are exclusively maternally inherited and thus originate from the oocyte. In this project we assume that obesity
induced alterations in oocyte or embryo mtDNA methylation patterns act as a mediator through which the metabolic stress memory is transferred
through the MT to the next generation, playing a key role in the mechanism of DOHaD. In the strategically designed MITOMEMORY project,
outbred Swiss mice will be fed an obesogenic diet and oocytes or early embryos will be collected to investigate the impact on mtDNA methylation
patterns which will be linked with mtDNA gene expression and bioenergetic functions. To further expand on the most sensitive window for the
induction of mtDNA methylation changes, also the relative importance of the uterine and lactation environment will be investigated by transferring
embryos from control or obese mice into control or obese recipients, using a 2*2 factorial design. Offspring somatic cell and oocyte mtDNA
methylation patterns will be examined and linked with metabolic health. The present project is supported by three expert supervisors and combines
unique interdisciplinary expertises to explore for the first time the fundamental importance of mitoepigenetics in the earliest life stages. Here, we
believe mitoepigenetics form a key pathway of the maternal inheritance of metabolic stress memory to the next generation. As an important first step
in developing science-based preventive and therapeutic strategies to sustainably improve metabolic health, this project forms an integral part of the
European Commission's political priorities (Horizon Europe Strategic Plan 2021-2024/2025-2027).
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