Selenium supplementation induces mitochondrial biogenesis in trophoblasts
Introduction
Placental oxidative stress is important in the aetiology of complications of pregnancy such as preeclampsia [1], [2] and pre-term labour [3]. Oxidative stress describes an imbalance between pro-oxidants such as reactive oxygen and nitrogen species (RONS) and anti-oxidants. Many anti-oxidants are present in our diet, and they are important in maintaining redox balance in all cells. However, they work at a 1:1 stoichiometry and are limited in the amount of RONS they can neutralize. Enzymatic anti-oxidants generally feature very high turnover rates, provide the ability to limit damaging effects of RONS, and are present in all cells [4].
The glutathione and thioredoxin systems are key components of the anti-oxidant network that provide such protection. Two members of these systems, glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) are seleno-proteins. They contain selenocysteine at their active site and are devoid of enzymatic activity in its absence [5]. The expression and activity of these enzymes is dependent on an adequate supply of either inorganic or organic selenium. For many years our research has focussed on the importance of these enzymes in cellular and animal models and exploring how an adequate selenium supply is correlated to initiation/progression of pathologies such a cardiovascular diseases [6] and complications of pregnancy [7], [8].
Mitochondria are central in the development of oxidative stress and cell survival is ultimately dependent on how mitochondria are able to counteract the production of RONS. This is a natural consequence of oxygen use during respiration, which is elevated during chronic hypoxia or during periods of ischemia and reperfusion [9]. Any perturbation to the flow of electrons through the electron transport chain or the provision of oxygen as the final electron acceptor exacerbates electron leakage and results in the generation of partially reduced forms of oxygen and nitrogen, which constitute RONS. In this context, we have previously investigated selenium supplementation as a means to increase anti-oxidant defences and thereby improve mitochondrial resilience to oxidative insult in the cause of pathologies characterised by enhanced oxidative stress, such as preeclampsia [7], [10].
Stressed mitochondria are able to return to normal function through anti-oxidant defences, by selectively removing damaged macromolecules and undergoing an elegant process of fusion and subsequent fission [11]. If recovery is not possible, damaged mitochondria will be removed by autophagy, or if the mitochondrial dysfunction is severe and widespread then the release of Cytochrome C will activate the intrinsic pathway to apoptosis and cell death [12]. This series of events is critical to cell turnover in the human placenta where mitochondrial oxidative stress has been shown to drive shedding of placental debris into the maternal circulation which may then elicit a hostile maternal immune response and endothelial cell activation which underpin the pathophysiology of disease such as preeclampsia [13], [14].
In previous investigations we have shown that selenium supplementation can protect trophoblasts from mitochondrial stress through the up regulation of anti-oxidant systems [7]. We hypothesized that selenium might also be improving cellular function by regulating mitochondrial biogenesis, possibly through the recently characterised selenoprotein H (Sel H), which has the capacity to up-regulate key components of the mitochondrial biogenesis pathways [15]. In the present study we aimed to investigate at what point/s in the electron transport system selenium had its effect, and to determine if the improvement in mitochondrial function was due to an increase in mitochondrial content, and if this might be regulated through Sel H. As trophoblasts form the feto–maternal interface and are critical in the transport of nutrients and oxygen to the developing fetus, mitochondrial content and functionality was examined in three trophoblast-like cell lines, and we have extended some of our observations into explants of placental tissues from first trimester pregnancies.
Section snippets
Cell culture
Culture of Swan-71, BeWo and JEG-3 cell lines was as previously described [7]. Cells were supplemented with 100 nM sodium selenite (Sigma, Australia) or 500 nM selenomethionine (ICN Chemicals, Australia) for 24 h.
Measurement of mitochondrial respiration in trophoblast-like cell lines
Mitochondrial respiration was measured in an Oxygraph-2k (Oroboros Instruments, Austria). Trophoblast-like cell lines were tested for routine respiration and respiration of different mitochondrial complexes as detailed in Supplementary Information.
qPCR for determination of mtDNA content
DNA was extracted using the Genomic
Selenium enhances mitochondrial respiration in trophoblast-like cell lines
Mitochondrial respiration was significantly higher in selenium (100 nM NaSe for 24 h) supplemented BeWo, JEG-3 and Swan-71 trophoblast-like cell lines compared to untreated controls in all states investigated (Fig. 1); indicating increased respiratory capacity with selenium supplementation in trophoblast-like cell lines. Initially, the respiration of intact BeWo, JEG-3 and Swan-71 cells was investigated; subsequently Swan-71 cells were permeabilized to determine mitochondrial complex-specific
Discussion
Our previous work has shown that selenium supplementation is effective in protecting trophoblasts from oxidative stress [7], [10]. The addition of selenium increased the expression and activity of key anti-oxidant selenoproteins, GPx and TrxR, boosting cellular defences and limiting the detrimental effects of RONS. Selenium supplementation was shown to be effective when the oxidative insult was applied exogenously, or generated endogenously by blocking the electron transport chain [7], [10].
Conflict of interest
The authors declare that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Acknowledgements
The authors would like to thank Anthony Hickey and Christopher Hedges, the University of Auckland, New Zealand. This research was funded through a Griffith University School of Medical Science Postgraduate Research Account.
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