Metabolic Disease Programming: From Mitochondria to Epigenetics, Glucocorticoid Signalling and Beyond

Abstract

Embryonic and foetal development are critical periods of development in which several environmental cues determine health and disease in adulthood. Maternal conditions and an unfavourable intrauterine environment impact foetal development and may programme the offspring for increased predisposition to metabolic diseases and other chronic pathologic conditions throughout adult life. Previously, non-communicable chronic diseases were only associated with genetics and lifestyle. Now the origins of non-communicable chronic diseases are associated with earlylife adaptations that produce long-term dysfunction. Early-life environment sets the long-term health and disease risk and can span through multiple generations. Recent research in developmental programming aims at identifying the molecular mechanisms responsible for developmental programming outcomes that impact cellular physiology and trigger adulthood disease. The identification of new therapeutic targets can improve offspring's health management and prevent or overcome adverse consequences of foetal programming. This review summarizes recent biomedical discoveries in the Developmental Origins of Health and Disease (DOHaD) hypothesis and highlight possible developmental programming mechanisms, including prenatal structural defects, metabolic (mitochondrial dysfunction, oxidative stress, protein modification), epigenetic and glucocorticoid signalling-related mechanisms suggesting molecular clues for the causes and consequences of programming of increased susceptibility of offspring to metabolic disease after birth. Identifying mechanisms involved in DOHaD can contribute to early interventions in pregnancy or 2 of 21 | GRILO et aL.

Angiotensin II type 1 receptor agonistic autoantibody blockade improves postpartum hypertension and cardiac mitochondrial function in rat model of preeclampsia

“…Additional studies are needed to establish the mechanism of action by which AT1-AA causes long term changes in the heart and how these are reversed by ‘n7AAc’. As with in utero stress on the fetus, epigenetic programing may be involved downstream of AT1 receptor activation by AT1-AA in the maternal heart [ 74 ], with ‘n7AAc’ attenuating this activation by serving as a “decoy receptor”.…”

Unravelling the impact of intrauterine growth restriction on heart development: insights into mitochondria and sexual dimorphism from a non-hominoid primate

“…Population and preclinical studies support the conclusion that epigenetics forms the link between in utero stress, such as MNR, hypoxia, maternal obesity, and hypertension, and the adult phenotype [1,2,23,42]. Epigenetics includes traditional factors, histone modifications (acetylations and methylations) and DNA methylations, as well as non-coding RNAs (ncRNAs).…”

“…Epigenetics includes traditional factors, histone modifications (acetylations and methylations) and DNA methylations, as well as non-coding RNAs (ncRNAs). The driving force for these changes has been ascribed to increased glucocorticoids and/or activity of the hypothalamic-pituitary-adrenal axes, in the case of MNR, as well as oxidative stress [1,2,42]. The study by Pereira et al raises the possibility that mitochondria are master regulators of both the remodeling and imprinting processes.…”

“…The study by Pereira et al raises the possibility that mitochondria are master regulators of both the remodeling and imprinting processes. Mitochondria are anticipated to affect genomic DNA methylation and histone acetylation, methylation, and phosphorylation via either coupling of the folate and methionine cycles or alterations in tricarboxylic acid (TCA) cycle metabolites, including α-ketoglutarate, succinate, and fumarate [42] (Figure 1). Increased ROS and decreased ATP are likely contributors as well.…”

General review of contents by Peter Nathanielsz

“…The next paper 'Metabolic Disease Programming: from Mitochondria to Epigenetics, Glucocorticoid Signaling and Beyond', by Grillo et al 10 , makes the very important point that mitochondria play a central role in foetal programming, by direct effects on both metabolism and induction of 1). There is also a crosstalk between mitochondria and epigenetic processes.…”