Mitochondrial dysfunction and epigenetic alterations in metabolically compromised oocytes : a key pathway to subfertility and a target to improve offspring health

The global rise in obesity, driven by high-fat/high-sugar diets, is increasingly linked to fertility issues in women and long-term health problems in their offspring. A key factor mediating these effects is the increased level of non-esterified fatty acids (NEFAs) in the ovarian and oviductal microenvironment, which imposes metabolic stress on the oocyte and early embryo. This stress is linked to mitochondrial dysfunction and epigenetic alterations. While the mitochondria’s influence on epigenetic programming in somatic cells (a process termed metaboloepigenetics) is well known, the direct relationship remains poorly understood in oocytes and early embryos. These cells exhibit unique mitochondrial characteristics and undergo dynamic epigenetic reprogramming. In this PhD research, we hypothesized that mitochondrial dysfunction in metabolically compromised oocytes and embryos affects epigenetic programming during early development, with potential long-term consequences for offspring health. Preconception dietary interventions aimed at improving oocyte mitochondrial function may prevent these outcomes. Using a bovine in vitro model, we showed that increased NEFAs during final oocyte maturation (and early embryo development) induce epigenetic alterations during early embryogenesis and on day 14 of development. Importantly, this was associated with mitochondrial dysfunction. Oocyte ATP production appears to play a crucial role in the mitochondrial-epigenetic link as specific inhibition of bovine oocyte ATP production during final oocyte maturation resulted in altered epigenetic programming in both the oocyte and early embryos. In a complementary in vivo outbred mouse model, we demonstrated that a long-term maternal high-fat/high-sugar diet from the preconception period until weaning (17 weeks) only moderately impacted offspring metabolic health and oocyte quality after being fed chow diet from weaning until adulthood. Switching the mothers to a control diet for four weeks before conception alleviated most of these effects. The novel insights from this research provide a foundation for further exploration of the mitochondrial-epigenetic link in oocytes and embryos under maternal metabolic stress conditions. These findings also offer potential avenues for developing in vitro or in vivo mitochondrial-targeted therapies to safeguard epigenetic programming and improve offspring health.