Placental mitochondria adapt developmentally and in response to hypoxia to support fetal growth

Sferruzzi‐Perri, Amanda N.; Higgins, J. Nicholas P.; Vaughan, Owen; Murray, Andrew J.; Fowden, Abigail L.

doi:10.1073/pnas.1816056116

Cited by 90 publications

(80 citation statements)

References 46 publications

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“…While further studies are needed to firmly establish a link between changes in bioenergetics in the male placenta and disturbances in fetal metabolic status, the co-occurrence of these phenomena suggest that they are related. Importantly, placental mitochondria are structurally and functionally diverse within the organ's regions and these mitochondrial subpopulations may also respond differently depending on gestational age [ 20 , 63 ]. Additional work is needed to elucidate how sex and specific placental cell populations interact to support fetal development.…”

Section: Discussionmentioning

confidence: 99%

“…Placental mitochondrial dysfunction has also been theorized to mediate sexually dimorphic fetal programming due to the mitochondria's importance in resource availability, oxidative stress, and steroidogenesis, as well as their relative abundance in the placenta [ 20 , 21 ]. Numerous studies have reported relationships between pregnancy complications and altered respiratory chain complex activity [ [22] , [23] , [24] ].…”

Section: Introductionmentioning

confidence: 99%

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Ozone-induced fetal growth restriction in rats is associated with sexually dimorphic placental and fetal metabolic adaptation

Miller

Dye

Henriquez

et al. 2020

Molecular Metabolism

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Objective The importance of the placenta in mediating the pre- and post-natal consequences of fetal growth restriction has been increasingly recognized. However, the influence of placental sexual dimorphism on driving these outcomes has received little attention. The purpose of this study was to characterize how sex contributes to the relationship between placental metabolism and fetal programming utilizing a novel rodent model of growth restriction. Methods Fetal growth restriction was induced by maternal inhalation of 0.8 ppm ozone (4 h/day) during implantation receptivity (gestation days [GDs] 5 and 6) in Long-Evans rats. Control rats were exposed to filtered air. At GD 21, placental and fetal tissues were obtained for metabolic and genomic assessments. Results Growth-restricted male placentae exhibited increased mitochondrial biogenesis, increased oxygen consumption, and reduced nutrient storage. Male growth-restricted fetuses also had evidence of reduced adiposity and downregulation of hepatic metabolic signaling. In contrast, placentae from growth-restricted females had elevated markers of autophagy accompanied by an observed protection against hepatic metabolic perturbations. Despite this, growth restriction in females induced a greater number of hypothalamic gene and pathway alterations compared to growth-restricted males. Conclusions Increases in mitochondrial metabolism in growth-restricted male placentae likely initiates a sequela of adaptations that promote poor nutrient availability and adiposity. Divergently, the female placenta expresses protective mechanisms that may serve to increase nutrient availability to support fetal metabolic development. Collectively, this work emphasizes the importance of sex in mediating alterations in placental metabolism and fetal programming.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ozone-induced fetal growth restriction in rats is associated with sexually dimorphic placental and fetal metabolic adaptation

Miller

Dye

Henriquez

et al. 2020

Molecular Metabolism

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“…Mitochondria are also important to trophoblast function, with alterations in trophoblast mitochondrial function evident in conditions associated with offspring obesity, including preeclampsia and gestation diabetes [91,92]. The decrease in trophoblast mitochondrial respiration in gestational diabetes seems mediated by an increase in ceramide [92], with ceramide also shown to increase mitochondrial fusion and mitophagy in preeclampsia trophoblasts [93].…”

Section: Melatonin and Mitochondriamentioning

confidence: 99%

“…In contrast, preeclampsia may be associated with an increase in trophoblast mitochondrial respiration, although with a decrease in respiratory reserve capacity [94]. Preclinical studies indicate that there may differential effects on mitochondrial function in different placental regions [91]. As well as immune cells, trophoblast mitochondrial function regulation by local and circadian melatonin are clearly relevant to placental changes that increase offspring obesity risk.…”

Section: Melatonin and Mitochondriamentioning

confidence: 99%

The Role of Prenatal Melatonin in the Regulation of Childhood Obesity

Ivanov

Evsyukova

Mazzoccoli

et al. 2020

Biology

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There is a growing awareness that pregnancy can set the foundations for an array of diverse medical conditions in the offspring, including obesity. A wide assortment of factors, including genetic, epigenetic, lifestyle, and diet can influence foetal outcomes. This article reviews the role of melatonin in the prenatal modulation of offspring obesity. A growing number of studies show that many prenatal risk factors for poor foetal metabolic outcomes, including gestational diabetes and night-shift work, are associated with a decrease in pineal gland-derived melatonin and associated alterations in the circadian rhythm. An important aspect of circadian melatonin’s effects is mediated via the circadian gene, BMAL1, including in the regulation of mitochondrial metabolism and the mitochondrial melatoninergic pathway. Alterations in the regulation of mitochondrial metabolic shifts between glycolysis and oxidative phosphorylation in immune and glia cells seem crucial to a host of human medical conditions, including in the development of obesity and the association of obesity with the risk of other medical conditions. The gut microbiome is another important hub in the pathoetiology and pathophysiology of many medical conditions, with negative consequences mediated by a decrease in the short-chain fatty acid, butyrate. The effects of butyrate are partly mediated via an increase in the melatoninergic pathway, indicating interactions of the gut microbiome with melatonin. Some of the effects of melatonin seem mediated via the alpha 7 nicotinic receptor, whilst both melatonin and butyrate may regulate obesity through the opioidergic system. Oxytocin, a recently recognized inhibitor of obesity, may also be acting via the opioidergic system. The early developmental regulation of these processes and factors by melatonin are crucial to the development of obesity and many diverse comorbidities.

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“…The adverse intrauterine environment caused by maternal malnutrition and placental hypoxia has been regarded as the main cause. 3,4 Growth restriction in fetuses causes lower birth weight and increased risk for the development of severe disorders later in life, such as mental illness, 5,6 obesity, cardiovascular, and renal disease. 7,8 According to previous studies on the Dutch Hunger Winter, early gestational exposure to the Dutch Hunger Winter of 1944-1945 was associated with an increased risk of schizophrenia in offspring, and the risk of schizophrenia was twice as high as that of the control group.…”

Section: Introductionmentioning

confidence: 99%

Fetal growth restriction mice are more likely to exhibit depression‐like behaviors due to stress‐induced loss of dopaminergic neurons in the VTA

Tian

Sun

et al. 2020

FASEB j.

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Fetal growth restriction (FGR) is a severe perinatal complication that can increase risk for mental illness. To investigate the mechanism by which FGR mice develop mental illness in adulthood, we established the FGR mouse model and the FGR mice did not display obvious depression‐like behaviors, but after environmental stress exposure, FGR mice were more likely to exhibit depression‐like behaviors than control mice. Moreover, FGR mice had significantly fewer dopaminergic neurons in the ventral tegmental area but no difference in serotoninergic neurons in the dorsal raphe. RNA‐seq analysis showed that the downregulated genes in the midbrain of FGR mice were associated with many mental diseases and were especially involved in the regulation of NMDA‐selective glutamate receptor (NMDAR) activity. Furthermore, the NMDAR antagonist memantine can relieve the stress‐induced depression‐like behaviors of FGR mice. In summary, our findings provide a theoretical basis for future research and treatment of FGR‐related depression.

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Placental mitochondria adapt developmentally and in response to hypoxia to support fetal growth

Cited by 90 publications

References 46 publications

Ozone-induced fetal growth restriction in rats is associated with sexually dimorphic placental and fetal metabolic adaptation

Ozone-induced fetal growth restriction in rats is associated with sexually dimorphic placental and fetal metabolic adaptation

The Role of Prenatal Melatonin in the Regulation of Childhood Obesity

Fetal growth restriction mice are more likely to exhibit depression‐like behaviors due to stress‐induced loss of dopaminergic neurons in the VTA

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