Review: Placental mitochondrial function and structure in gestational disorders
Introduction
Mitochondria originated from the symbiosis of primordial eukaryotic cells and aerobic bacteria. Mitochondria, which contain their own genome (mtDNA) and machinery to synthesise RNA and proteins, work in concert with the nuclear genome and other organelles. Almost all cellular energy is produced through oxidative phosphorylation in mitochondria; partnered redox reactions transfer electrons through oxygen to water and pump protons into the mitochondrial intermembrane membrane space through respiratory complexes (complexes I, III, and IV). The electrochemical gradient created by the transfer of protons is termed mitochondrial membrane potential (ΔΨm), and is harnessed by ATP synthase (complex V) to generate ATP. Mitochondria are known as the powerhouses of the cell due to their central role in ATP generation. However, mitochondria have several additional functions; they provide important signalling on cellular homeostasis, and are key regulators of cell fate through autophagy/apoptosis. Mitochondria form a dynamic reticulum, and the reshaping of this reticulum in response to differences in mitochondrial membrane potential helps control mitochondrial and cellular fate (Fig. 1). In conjunction with the endoplasmic reticulum, mitochondria can regulate mediators of cell death such as calcium levels and caspases. Additionally, in the placenta and other tissues such as the adrenal glands, mitochondria are crucial to the production of steroids [1], [2].
Mitochondrial dysfunction is thought to contribute to a wide range of disorders related to oxidative stress, such as cardiovascular disease, type 2 diabetes, and neurodegenerative disorders. Partial occlusion of blood flow leading to local hypoxia is a common feature in several pathologies which show effects on the mitochondria. Mitochondria consume oxygen to generate ATP via oxidative phosphorylation, producing reactive oxygen species (ROS) as a by-product. Oxygen variability can lead to oxidative stress when there is a disproportionately high production of ROS in comparison to antioxidants [3], [4]. Mitochondria are susceptible to damage by these free radicals, which may result in alterations in their structure and function [5].
Pregnancy itself is characterised by increased oxidative stress, which is often heightened in disorders. Of relevance to this review, increased placental oxidative stress is a feature of several gestational pathologies including preeclampsia, intrauterine growth restriction (IUGR), maternal diabetes, and maternal obesity [6]. Preeclampsia and IUGR are associated with reduced placental perfusion, potentially leading to oxygen deprivation [7]. Placentae afflicted by maternal diabetes and/or obesity are exposed to a range of insults, including high glucose and fatty acid levels as well as inflammatory mediators. These insults may lead to abnormal function of the uteroplacental unit, including impaired placentation [8]. As a number of pregnancy pathologies share a mutual phenotype of restricted or heightened variability in placental oxygen supply [9], which is likely to alter mitochondrial structure and function [10], [11], placental mitochondria may be aetiologically important in several pregnancy pathologies.
This review details important features of placental mitochondria and summarises evidence on how placental mitochondria are affected in a range of pregnancy disorders. Gaining a greater appreciation of mitochondrial content, structure, and function in the placenta provides an opportunity to explore interventional avenues.
Section snippets
Mitochondria reactive oxygen species
Oxidative stress mediated by ROS is a common feature of several gestational disorders. Mitochondria are the main sites of ROS generation, and are also susceptible to ROS-mediated damage. The generation of ROS result from the transfer of a single electron from a redox donor to molecular oxygen, yielding superoxide which can be converted to hydrogen peroxide by superoxide dismutase. This often occurs when oxygen reacts with electrons generated by complex I and III but can also occur at complex II
Mitochondrial regulation of apoptosis
Mitochondria are key signalling organelles due to their responsiveness to the metabolic functioning of the cell. The interactions between mitochondria and the endoplasmic reticulum are critical to cell homeostasis and signalling (reviewed by Ref. [18]). Mitochondria can initiate apoptosis by the release of mitochondrial intermembrane space proteins such as cytochrome c into the cytoplasm through mitochondrial membrane permeabilization or rupture [21]. An early event in the initiation of
Mitochondrial content
Cells contain multiple mitochondria arranged in a dynamic interconnected reticulum. The mitochondrial content or mass in cells is plastic and able to respond to a wide variety of stimuli such as caloric restriction, increased energy demands, and various disease states [35], [36], [37], [38]. In the placenta, pregnancy pathologies related to placental insufficiency including IUGR and preeclampsia, as well as maternal diabetes and obesity, are associated with changes in mitochondrial content (
Syncytiotrophoblast mitochondria
As well as generating cellular energy in the form of ATP from oxidative phosphorylation, mitochondria are important in the synthesis of steroid hormones (reviewed in the placenta by Ref. [2]). In the human placenta, the syncytiotrophoblast forms the interface between maternal and fetal systems. Progesterone synthesised by the syncytiotrophoblast from maternally-derived cholesterol is central to the establishment and maintenance of the pregnancy. Progesterone functions in modulation of the
Mitochondria in preeclampsia and intrauterine growth restriction
Preeclampsia is a hypertensive disorder of pregnancy characterised by maternal endothelial dysfunction. Both preeclampsia and IUGR are associated with reduced/intermittent placental perfusion and increased oxidative stress [3], [71]. As detailed earlier in this review, preeclampsia and IUGR can lead to changes in placental apoptosis, mitochondrial fission/fusion, and mitochondrial content (Table 1). Additionally, proteomic analysis of placental tissue from preeclamptic pregnancies shows the
Mitochondria in maternal diabetes
High circulating glucose concentrations in maternal diabetes, which includes both pre-existing diabetes and GDM, may adversely impact on placental function. In individuals with diabetes, there are ample studies reporting alterations in mitochondrial content, respiratory function, and complex activity in non-gestational tissues. However, studies examining specific mitochondrial changes in the placenta are limited. In whole placentae from women with type 1 diabetes, activity of complexes I and
Mitochondria in obesity
Obesity is associated with excess circulating fatty acids, which can affect placental mitochondrial function [81]. Mitochondrial content, as measured in mitochondrial DNA amount, is decreased in placentae from obese women, although when measured by citrate synthase activity, is unaltered [49]. This suggests that despite a lower mitochondrial number, the oxidative capacity of the mitochondria to produce ATP remains the same.
The lower mitochondrial content is, however, associated with lower
Conclusion
Mitochondria are critical to cellular viability, and mitochondrial function can be disturbed by variability in oxygen supply. Reduced/interment blood flow to the placenta resulting in oxidative stress is thought to be a common feature of several pregnancy complications, and this oxidative stress is likely to affect placental mitochondria. Indeed, placental mitochondrial function is altered in a number of pregnancy disorders. Whilst the majority of studies observed an increase in oxidative
Conflicts of interest
The authors have no conflicts of interest to declare.
Acknowledgements
This review was generated as part of the Queensland Perinatal Consortium Inaugural Conference held on July 15th 2016 in Brisbane, Queensland Australia. The conference was supported by an Intra-Faculty Collaborative Workshop grant from the Faculty of Medicine, The University of Queensland.
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