A maternal high-fat, high-sucrose diet induces transgenerational cardiac mitochondrial dysfunction independently of maternal mitochondrial inheritance

Abstract

Maternal obesity is correlated with cardiovascular disease in offspring, with a 1.3-fold increase in events observed in offspring of obese women. We have observed that obesity-exposed oocytes demonstrate impaired mitophagy and transmit damaged mitochondria to the offspring. Accordingly, we hypothesized that maternal obesity induces cardiac mitochondrial dysfunction in the offspring via transgenerational inheritance of abnormal oocyte mitochondria. We mated female mice fed a high-fat/high-sucrose (HFS) diet (or chow) with chow-fed males and assessed cardiac structure and function in their descendants that were chow fed in each generation. All F1 to F3 descendants bred via the female in each generation were nonobese and demonstrated cardiac mitochondrial abnormalities with crystal rarefaction and reduced oxygen consumption pointing to a transgenerational effect, while obese F0 dams’ hearts were unaffected. Furthermore, male offspring from F1 to F3 generations and female F1 and F2 offspring developed increased left ventricular (LV) mass (vs. chow-fed controls). Increased LV mass was also observed in offspring generated by in vitro fertilization of obesity-exposed oocytes and gestation in nonobese surrogates, ruling out a gestational environment effect. Contrary to our hypothesis, male F1 also transmitted these effects to their offspring, ruling out maternal mitochondria as the primary mode of transmission. We conclude that transmission of obesity-induced effects in the oocyte nucleus rather than abnormal mitochondria underlie transgenerational inheritance of cardiac mitochondrial defects in descendants of obese females. These findings will spur exploration of epigenetic alterations in the oocyte genome as potential mechanisms whereby a family history of maternal obesity predisposes to cardiovascular disease in humans. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/maternal-obesity-induces-transgenerational-cardiac-mitochondrial-dysfunction/ .

Listening to mother: Long‐term maternal effects in mammalian development

“…These results indicate that correct regulation of oocyte mitochondrial gene activity, mitochondrial function, and cellular reactive oxygen species production may be key for generating high‐quality oocytes, which in turn support long‐term development of healthy progeny. A recent study also provided evidence for an epigenetic effect of maternal diet on progeny cardiac mitochondrial function in mice (Ferey et al, 2019).…”

“…The health and development of the mitochondria, which are exclusively matrilineally transmitted, are critical for oocyte quality and long‐term embryo viability, as well as diverse aspects of progeny phenotype. The oocyte mitochondrial legacy can have a large impact on long‐term embryo development, adult phenotype, and even transgenerational effects in progeny health (Andreas et al, 2019; Ferey et al, 2019; St John et al, 2019; Udagawa & Ishihara, 2019). Through ATP production, oocyte mitochondria not only support essential metabolic and homeostatic needs of the oocyte and early embryo, but also provide the energy required for meiosis, the vast amount of genome reprogramming that occurs, DNA replication and repair, and the production of the glutathione that is needed for mitigating effects of ROS.…”

“…But the changes in oocyte mitochondrial dynamics have long‐term effects as well as immediate effects on the oocyte and early embryo energetics. One striking series of studies found that a high‐fat/high‐sucrose maternal diet can damage oocyte mitochondria (Boudoures et al, 2017; Grindler & Moley, 2013; Saben et al, 2016), and that this can lead to changes in cardiac mitochondrial structure and function for multiple generations (Ferey et al, 2019), as well as oocyte and skeletal muscle effects (Andreas et al, 2019; Saben et al, 2016). Thus, correct regulation of a healthy oocyte mitochondrial legacy contributes to long‐term healthy progeny phenotype.…”

“…The scope and impacts of these less immediate and less direct maternal effects continue to be discovered. Such maternal effects are also taking on new and expanding importance as researchers endeavor to understand the oocyte's role in developmental origins of health and disease (DOHaD), particularly in the context of maternal health and nutrition effects on oocyte quality (Andreas, Reid, Zhang, & Moley, 2019; Matorras et al, 2020) and, for example, adult cardiovascular disease (Ferey et al, 2019; Velazquez, Fleming, & Watkins, 2019). Not only might the environment impact the oocyte, and thereby lead to short‐ and long‐term effects on embryogenesis, but genetic variation in the inherent features of oocytes may also determine the responses of oocytes and embryos to different environmental factors and stressors.…”

Maternal transmission of mitochondrial diseases

“…Among the factors that contribute with maternal transmission of metabolic diseases, mitochondria are a main candidate giving their maternal-exclusive inheritance. In fact, mitochondrial defects in somatic tissues have been associated with obesity, diabetes and cardiovascular disease (Silva et al, 2000;Sarparanta et al, 2017;Ferey et al, 2019). For instance, mtDNA mutations impacting mitochondrial function and ATP production link with abnormal insulin release and b-cell development, insulin resistance, and diabetes (Poulton et al, 1998;Silva et al, 2000;Kaufman et al, 2015).…”