Sex-dependent vulnerability of fetal nonhuman primate cardiac mitochondria to moderate maternal nutrient reduction

Abstract

Poor maternal nutrition in pregnancy affects fetal development, predisposing offspring to cardiometabolic diseases. The role of mitochondria during fetal development on later-life cardiac dysfunction caused by maternal nutrient reduction (MNR) remains unexplored. We hypothesized that MNR during gestation causes fetal cardiac bioenergetic deficits, compromising cardiac mitochondrial metabolism and reserve capacity. To enable human translation, we developed a primate baboon model (Papio spp.) of moderate MNR in which mothers receive 70% of control nutrition during pregnancy, resulting in intrauterine growth restriction (IUGR) offspring and later exhibiting myocardial remodeling and heart failure at human equivalent ∼25 years. Term control and MNR baboon offspring were necropsied following cesarean-section, and left ventricle (LV) samples were collected. MNR adversely impacted fetal cardiac LV mitochondria in a sex-dependent fashion. Increased maternal plasma aspartate aminotransferase, creatine phosphokinase (CPK), and elevated cortisol levels in MNR concomitant with decreased blood insulin in male fetal MNR were measured. MNR resulted in a two-fold increase in fetal LV mitochondrial DNA (mtDNA). MNR resulted in increased transcripts for several respiratory chain (NDUFB8, UQCRC1, and cytochrome c) and adenosine triphosphate (ATP) synthase proteins. However, MNR fetal LV mitochondrial complex I and complex II/III activities were significantly decreased, possibly contributing to the 73% decreased ATP content and increased lipid peroxidation. MNR fetal LV showed mitochondria with sparse and disarranged cristae dysmorphology. Conclusion: MNR disruption of fetal cardiac mitochondrial fitness likely contributes to the documented developmental programming of adult cardiac dysfunction, indicating a programmed mitochondrial inability to deliver sufficient energy to cardiac tissues as a chronic mechanism for later-life heart failure.

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

“…The study by Pereira et al [13] is the first report that MNR impacts fetal cardiac LV mitochondria, in a close evolutionary relative to humans, and in a sex-dependent fashion. The basis for the protection in females needs to be defined.…”

“…It is difficult to interpret what the particular pattern of altered mitochondrial proteins represents, particularly in the context of what has been reported for differential mitochondrial protein expression in other studies, for instance related to aging [35][36][37]. However, Pereira et al did observe that LV mitochondrial complex I and complex II/III activities were significantly decreased by MNR in males and in male and female fetuses, respectively [13]. Consistent with that, LV ATP content was decreased by 73% in MNR fetuses, mostly in males.…”

“…Numerous animal studies have affirmed this relationship as well, demonstrating in many cases an impact in particular of fetal stress on heart development [10][11][12]. In a remarkable study appearing recently in Clinical Science, Pereira et al reported findings on the impact of MNR on the fetal heart using baboons [13]. Their findings are obviously of great interest given the fact that baboons are close evolutionary relatives to humans, but also for providing mechanistic insights into the programing process that underlies the DOHaD hypothesis.…”

“…The recent study of Pereira et al in Clinical Science is noteworthy for its detailed analysis of the impact of MNR on LV mitochondria and the finding of sexual dimorphism in the process [13]. Analyses were performed on near-term fetuses (0.9 gestation) of mothers fed a control diet or who received 70% of control nutrition for most of the pregnancy (from 0.16 gestation).…”

“…Notably, the latter has been associated with ROS generation [37]. Pereira et al did report indirect evidence for increased oxidative stress and lipid peroxidation [13]. LV malondialdehyde (MDA) levels were increased by MNR, most notably in male fetuses.…”