Research Patricia Kubo Fontes

Abstract

Obesity in women not only impairs health and fertility but also increases the risk of metabolic disorders and obesity in subsequent generations. Using a diet-induced obese mouse model, we demonstrated that oocyte mitochondrial dysfunction plays a central role in the pathogenesis of reduced oocyte quality and may also contribute to intergenerational effects by transmitting dysfunctional mitochondria to the offspring's oocytes and somatic cells, potentially leading to long-term consequences for offspring health. Mitochondrial function is crucial not only for cellular energy production but also for regulating key biological processes such as apoptosis. Notably, several unique features of mitochondria make their proper function particularly critical for maintaining health. All mitochondria are maternally inherited and therefore originate from the oocyte. Moreover, mitochondria contain their own genome (mtDNA), which can undergo epigenetic modifications, including DNA methylation. Our research group has therefore focused on testing the hypothesis that obesity-induced alterations in oocyte and embryo mtDNA methylation (mtDNAm) patterns act as mediators through which metabolic stress memory is transmitted to the next generation, thereby increasing the risk of obesity in the offspring. Building on an ongoing research program that investigates mtDNA methylation profiles in oocytes and embryos across mouse generations, this BOF-SRG project is strategically designed to complement that work by examining whether the mtDNAm profile in liver tissue is associated with an increased risk of obesity in offspring born to obese mothers. To the best of our knowledge, expertise in mtDNAm analysis is currently unavailable within the UAntwerp research community. This underscores the need for methodological standardization at the foundational level—both for the success of this project and for advancing related research lines at UAntwerp. Accordingly, this BOF-SRG proposal aims to develop a method to assess mtDNAm using Oxford Nanopore Technology sequencing, in collaboration with the UAntwerp core facilities, to characterize the mitochondrial epigenetic signature in the liver tissue of offspring born to obese mothers. Through this approach, we aim to determine whether an abnormal mtDNAm profile in the liver is associated with an increased risk of obesity in offspring born to obese mothers. To test this, embryos from control or obese mice will be transferred to control or obese recipients using a 2 × 2 factorial design. This setup isolates the effects of the uterine and lactation environments, allowing for the evaluation of intergenerational influences of maternal obesity. Overall, this project will explore the fundamental importance of mitoepigenetics from the earliest stages of life to adulthood in the next generation. We propose that mitoepigenetic regulation represents a key pathway for the maternal inheritance of metabolic stress memory. As a crucial first step toward science-based preventive and therapeutic strategies to sustainably improve metabolic health, this project aligns closely with the European Commission's political priorities outlined in the Horizon Europe Strategic Plan 2025–2027.

Researcher(s)

• Promoter: Kubo Fontes Patricia

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

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).

Researcher(s)

• Promoter: Leroy Jo
• Fellow: Kubo Fontes Patricia

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project