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Placental energy metabolism in health and disease—significance of development and implications for preeclampsia

  • Irving L.M.H. Aye
    Correspondence
    Corresponding author: Irving L.M.H. Aye, PhD.
    Affiliations
    Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom

    Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom

    National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, University of Cambridge, United Kingdom
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  • Catherine E. Aiken
    Affiliations
    Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom

    National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, University of Cambridge, United Kingdom
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  • D. Stephen Charnock-Jones
    Affiliations
    Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom

    Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom

    National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, University of Cambridge, United Kingdom
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  • Gordon C.S. Smith
    Affiliations
    Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom

    Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom

    National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, University of Cambridge, United Kingdom
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Open AccessPublished:November 12, 2020DOI:https://doi.org/10.1016/j.ajog.2020.11.005
      The placenta is a highly metabolically active organ fulfilling the bioenergetic and biosynthetic needs to support its own rapid growth and that of the fetus. Placental metabolic dysfunction is a common occurrence in preeclampsia although its causal relationship to the pathophysiology is unclear. At the outset, this may simply be seen as an “engine out of fuel.” However, placental metabolism plays a vital role beyond energy production and is linked to physiological and developmental processes. In this review, we discuss the metabolic basis for placental dysfunction and propose that the alterations in energy metabolism may explain many of the placental phenotypes of preeclampsia such as reduced placental and fetal growth, redox imbalance, oxidative stress, altered epigenetic and gene expression profiles, and the functional consequences of these aberrations. We propose that placental metabolic reprogramming reflects the dynamic physiological state allowing the tissue to adapt to developmental changes and respond to preeclampsia stress, whereas the inability to reprogram placental metabolism may result in severe preeclampsia phenotypes. Finally, we discuss common tested and novel therapeutic strategies for treating placental dysfunction in preeclampsia and their impact on placental energy metabolism as possible explanations into their potential benefits or harm.

      Key words

      Introduction

      The placenta plays a vital role in the development and severity of preeclampsia. It has long been established that the presence of the placenta and not the fetus is necessary for preeclampsia. For example, molar pregnancies are susceptible to preeclampsia and the syndrome resolves on removal of the placenta.
      • Jauniaux E.
      Partial moles: from postnatal to prenatal diagnosis.
      The prevailing hypothesis for the cause of preeclampsia centers on defective placentation and placental dysfunction. As such, preeclampsia shares common pathophysiology with other “disorders of placentation” often referred to as the “great obstetrical syndromes” that include spontaneous miscarriage, placental abruption, and fetal growth restriction (FGR).
      • Brosens I.
      • Pijnenborg R.
      • Vercruysse L.
      • Romero R.
      The “great obstetrical syndromes” are associated with disorders of deep placentation.
      Defective placentation in preeclampsia is characterized by abnormal trophoblast invasion and remodeling of the spiral arteries by extravillous trophoblast. Deficient spiral artery remodeling leads to a failure to establish an appropriate uteroplacental blood supply and therefore is thought to give rise to trophoblast damage that may be accompanied by an ischemia-reoxygenation type of injury
      • Burton G.J.
      • Woods A.W.
      • Jauniaux E.
      • Kingdom J.C.P.
      Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.
      and placental stress (oxidative, endoplasmic reticulum [ER], and inflammatory). The maternal peripheral endothelial activation and systemic inflammatory response are then triggered by placentally released factors associated with placental stress.
      Perturbations in placental metabolism and oxidative stress are universally observed in preeclampsia, although the cause-and-effect relationship is not clear. Placental energy metabolism intermediates are inversely correlated with levels of placenta-released soluble fms-like tyrosine kinase 1 (sFlt-1),
      • Austdal M.
      • Thomsen L.C.V.
      • Tangerås L.H.
      • et al.
      Metabolic profiles of placenta in preeclampsia using HR-MAS MRS metabolomics.
      suggesting that the deficiency in energy metabolism correlates with preeclampsia severity. In this review, we provide an overview of our understanding of the placental central energy metabolic pathways and their multifaceted contributions to cellular processes. We highlight the emerging role of metabolic intermediates as cell signaling and epigenetic modifiers and the significance of these links during placental development and implications for preeclampsia.

      Central Carbon Metabolism—Contributions to Adenosine Triphosphate and Beyond

      Central carbon metabolism describes the series of reactions that result in the transformation of nutrients into compounds containing high-energy phosphate bonds such as adenosine triphosphate (ATP). An overview of the metabolic pathways contributing to ATP generation is shown in Figure 1. In addition to fulfilling the bioenergetic functions of the cell, the metabolic intermediates, cofactors, and cosubstrates generated by these reactions also provide biosynthetic precursors, balance reducing equivalents, and orchestrate the management of reactive oxygen species (ROS). Moreover, there is growing evidence of a role for these metabolic intermediates in regulating signal transduction and gene control through transcriptional and epigenetic processes.
      Figure thumbnail gr1
      Figure 1Central carbon metabolism and its contribution to bioenergetic and biosynthetic processes
      Key metabolic pathways involved in the generation of ATP and biosynthetic precursors from nutrients. The description of the metabolic pathways is discussed in the main text. The glycolytic shunt pathways: pentose phosphate pathway and hexosamine biosynthetic pathway are shaded in yellow and pink, respectively. Cofactors are depicted in blue and orange, and biosynthetic precursors are shown in red.
      acetyl-CoA, acetyl coenzyme A; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoQ, coenzyme Q; Cyt c, cytochrome C; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; malonyl-CoA, malonyl coenzyme A; NAD+, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; TCA, tricarboxylic acid.
      Aye. Placental metabolism in preeclampsia. Am J Obstet Gynecol 2022.

      Bioenergetics

      The placenta produces approximately 5 μmol of ATP per gram of tissue per minute from glucose,
      • Bax B.E.
      • Bloxam D.L.
      Energy metabolism and glycolysis in human placental trophoblast cells during differentiation.
      ,
      • Carter A.M.
      Placental oxygen consumption. Part I: in vivo studies--a review.
      which is equivalent to >2.5 kg of ATP per day in a term placenta. This metabolic activity is required to meet the high ATP demand of many energetically demanding tasks, such as nutrient transport and protein synthesis which constitute >50% of the total ATP consumption.
      • Carter A.M.
      Placental oxygen consumption. Part I: in vivo studies--a review.
      ,
      • Hay Jr., W.W.
      Energy and substrate requirements of the placenta and fetus.
      To support maternal cardiometabolic adaptations to pregnancy, the placenta secretes large quantities of hormones into the maternal circulation, a process that requires considerable ATP input. For example, human placental lactogen (hPL) production by the term placenta reaches 1 to 4 g/d,
      • Gusseck D.J.
      Role of nucleic acids in the regulation of human placental lactogen synthesis.
      which requires approximately 366 mg of ATP for hPL protein synthesis.
      • Stouthamer A.H.
      A theoretical study on the amount of ATP required for synthesis of microbial cell material.
      Therefore, high ATP-consuming processes such as protein synthesis
      • Yung H.W.
      • Calabrese S.
      • Hynx D.
      • et al.
      Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction.
      and nutrient transport
      • Baumann M.
      • Körner M.
      • Huang X.
      • Wenger F.
      • Surbek D.
      • Albrecht C.
      Placental ABCA1 and ABCG1 expression in gestational disease: pre-eclampsia affects ABCA1 levels in syncytiotrophoblasts.
      ,
      • Lüscher B.P.
      • Marini C.
      • Joerger-Messerli M.S.
      • et al.
      Placental glucose transporter (GLUT)-1 is down-regulated in preeclampsia.
      are impaired in placentas with preeclampsia with ensuing FGR.
      Glucose is the major nutrient source for energy generation in the placenta. Approximately 50% of the glucose taken up from the maternal circulation is oxidized in the placenta, and only 20% transferred to the fetus with the remainder metabolized into lactate.
      • Gu W.
      • Jones C.T.
      • Harding J.E.
      Metabolism of glucose by fetus and placenta of sheep. The effects of normal fluctuations in uterine blood flow.
      Glucose metabolism by glycolysis generates pyruvate with a net gain of 2 ATP molecules.
      This pyruvate is transported into the mitochondria and feeds into the tricarboxylic acid (TCA) cycle after oxidation into acetyl coenzyme A (acetyl-CoA) either as citrate or oxaloacetate. In addition to glucose, fatty acids and amino acids provide alternative fuel sources to feed into the TCA cycle via their conversion into the metabolic intermediate acetyl-CoA. In the TCA cycle, only 1 ATP molecule is generated for each acetyl-CoA, but the iterative oxidation reactions produce reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which function as electron carriers to establish the proton gradient that drives ATP production through oxidative phosphorylation (OXPHOS) in the electron transport chain (ETC). Theoretically, 1 molecule of NADH and FADH2 produces 2.5 and 1.5 ATP molecules, respectively. However, in practice, this is considerably less owing to energy consumption by active mitochondrial transport of substrates (eg, pyruvate, phosphate, and adenosine diphosphate [ADP]) used during mitochondrial metabolism and by mitochondrial proton leak.
      • Divakaruni A.S.
      • Brand M.D.
      The regulation and physiology of mitochondrial proton leak.
      Under aerobic conditions, pyruvate metabolism provides the link between glycolysis and the TCA cycle. Lactate is also reversibly converted from pyruvate by lactate dehydrogenase (LDH), and this reaction was traditionally believed to occur only under anaerobic conditions resulting in the removal of lactate into the blood. However, this long-held view of lactate as a metabolic waste product has since been revised.
      • Rabinowitz J.D.
      • Enerbäck S.
      Lactate: the ugly duckling of energy metabolism.
      • Robergs R.A.
      • McNulty C.R.
      • Minett G.M.
      • Holland J.
      • Trajano G.
      Lactate, not lactic acid, is produced by cellular cytosolic energy catabolism.
      • Hui S.
      • Ghergurovich J.M.
      • Morscher R.J.
      • et al.
      Glucose feeds the TCA cycle via circulating lactate.
      In vivo metabolic tracing using stable isotopes in nonpregnant mice indicates that the contribution of 13C-lactate toward TCA cycle metabolism is greater than 13C-glucose in all tissues except the brain.
      • Hui S.
      • Ghergurovich J.M.
      • Morscher R.J.
      • et al.
      Glucose feeds the TCA cycle via circulating lactate.
      In vivo studies of the human fetal-placental metabolism are not possible, but studies in pregnant ewes using radioactive tracers indicate that 30% of the glucose from the maternal circulation is converted into lactate by the placenta.
      • Aldoretta P.W.
      • Hay Jr., W.W.
      Effect of glucose supply on ovine uteroplacental glucose metabolism.
      This naturally raises the question of why so much of placental glucose metabolism is invested in generating lactate under normoxic conditions. First, the reduction of pyruvate to lactate by LDH regenerates nicotinamide adenine dinucleotide (NAD+), allowing glycolytic flux to be maintained. In the absence of lactate, glycolysis must be tightly coupled with the TCA cycle, such that every molecule of NADH and pyruvate produced by glycolysis is cleared by mitochondrial metabolism.
      • Rabinowitz J.D.
      • Enerbäck S.
      Lactate: the ugly duckling of energy metabolism.
      Thus, the production of lactate uncouples these pathways so that they can occur independently, and it serves as a universal metabolic fuel source feeding into both the placenta and the fetus. Lactate produced by the placenta accounts for as much as 25% of fetal oxidative metabolism in sheep,
      • Burd L.I.
      • Jones Jr., M.D.
      • Simmons M.A.
      • Makowski E.L.
      • Meschia G.
      • Battaglia F.C.
      Placental production and foetal utilisation of lactate and pyruvate.
      and reduced placental lactate transport to the fetus is associated with FGR.
      • Settle P.
      • Sibley C.P.
      • Doughty I.M.
      • et al.
      Placental lactate transporter activity and expression in intrauterine growth restriction.

      Biosynthetic processes

      The intermediates of energy metabolism are also essential for the biosynthesis of nucleotides, fatty acids, cholesterol, and amino acids to form biomass (Figure 1). Glycolysis acts as a metabolic hub connecting with its branched pathways to generate biosynthetic precursors. Glucose 6-phosphate can be diverted into the pentose phosphate pathway (PPP) to generate ribose 5-phosphate, a nucleotide precursor. Fructose 6-phosphate branches off into the hexosamine biosynthetic pathway (HBP) to generate uridine diphosphate N-acetylglucosamine (UDP-glcNAc), a key substrate for protein glycosylation. Dihydroxyacetone phosphate (DHAP) interconversion from fructose-bisphosphate provides the glycerol backbone necessary for triglyceride synthesis. Finally, 3-phosphoglycerate can be used for serine and glycine synthesis, providing a source of methyl groups for one-carbon metabolic pathways that generate purines and glutathione.
      TCA cycle intermediates are also biosynthetic precursors. When these metabolites are transported to the cytosol, they exhibit different metabolic functions compared with the mitochondria. Citrate is exported from the mitochondria into the cytosol and converted into acetyl-CoA. Although mitochondrial acetyl-CoA is used to generate energy, cytosolic acetyl-CoA is metabolized into fatty acids or condensed in the mevalonate pathway to produce cholesterol and subsequently steroids.
      The use of TCA cycle metabolites in biosynthetic pathways requires that carbon be resupplied to the cycle and intermediate pools maintained. This is achieved through anaplerosis, that is, the influx of metabolic intermediates into pathways to replace those used for biosynthesis. These anaplerotic pathways replenish TCA cycle metabolites at sites other than acetyl-CoA. The mitochondrial export of citrate results in a decline in alpha-ketoglutarate (α-KG), which is compensated for by glutaminolysis. In most tissues, this involves the extracellular uptake of glutamine and its conversion into glutamate by glutaminase (GLS), and subsequent metabolism into α-KG. However, the placenta and the fetus coordinate a system of partitioning glutamate and glutamine between the different units (Figure 2). The placenta lacks GLS activity,
      • Remesar X.
      • Arola L.
      • Palou A.
      • Alemany M.
      Activities of enzymes involved in amino-acid metabolism in developing rat placenta.
      ,
      • Self J.T.
      • Spencer T.E.
      • Johnson G.A.
      • Hu J.
      • Bazer F.W.
      • Wu G.
      Glutamine synthesis in the developing porcine placenta.
      and therefore, the majority of the glutamine taken up by the placenta is transferred to the fetus and accounts for up to 80% of the fetal glutamine, the remainder of which is derived from de novo fetal synthesis.
      • Day P.E.L.
      • Cleal J.K.
      • Lofthouse E.M.
      • et al.
      Partitioning of glutamine synthesised by the isolated perfused human placenta between the maternal and fetal circulations.
      The fetal reliance on placental glutamine delivery may explain why neonates with deficiency in glutamine synthetase (GS), which synthesizes glutamine from glutamate, survive in utero development but die shortly after birth.
      • Roifman M.
      • Niles K.M.
      • MacNeil L.
      • et al.
      Homozygous GLUL deletion is embryonically viable and leads to glutamine synthetase deficiency.
      In contrast, there is no net placental transfer of glutamate from the mother to the fetus. In fact, glutamate is transferred from the fetus to the placenta. Fetal glutamine is metabolized by the fetal liver into glutamate, and up to 90% of this is taken back up by the placenta.
      • Moores Jr., R.R.
      • Vaughn P.R.
      • Battaglia F.C.
      • Fennessey P.V.
      • Wilkening R.B.
      • Meschia G.
      Glutamate metabolism in fetus and placenta of late-gestation sheep.
      ,
      • Battaglia F.C.
      Glutamine and glutamate exchange between the fetal liver and the placenta.
      Placental glutamate is then converted back into glutamine by GS or metabolized into α-KG by glutamate dehydrogenase forming the anaplerotic reactions to replenish the TCA cycle.
      • Day P.E.L.
      • Cleal J.K.
      • Lofthouse E.M.
      • et al.
      Partitioning of glutamine synthesised by the isolated perfused human placenta between the maternal and fetal circulations.
      This pathway highlights the importance of placental and fetal interrelationships in regulating key aspects of placental metabolism.
      Figure thumbnail gr2
      Figure 2Placental-fetal glutamine-glutamate shuttle
      Owing to the absence of the glutaminase enzyme, placental glutamine metabolism requires the input of fetal liver enzymes to convert glutamine to glutamate which is then reextracted by the placenta from the fetal circulation. Glutamate is converted back to glutamine or α-ketoglutarate which provides the substrate for TCA anaplerosis.
      GLS, glutaminase; GLUD, glutamate dehydrogenase; GS, glutamine synthetase; TCA, tricarboxylic acid.
      Aye. Placental metabolism in preeclampsia. Am J Obstet Gynecol 2022.

      Redox homeostasis and reactive oxygen species

      Mitochondrial ETC is a major source of cellular ROS, arising from complexes I and III (Figure 3). During normal mitochondrial function, as many as 2% of electrons leak from the ETC and reduce oxygen to superoxide (O2•−).
      • Jastroch M.
      • Divakaruni A.S.
      • Mookerjee S.
      • Treberg J.R.
      • Brand M.D.
      Mitochondrial proton and electron leaks.
      O2•− can be dismutated to produce hydrogen peroxide (H2O2), which in turn may be partially reduced to form hydroxyl radicals (OH•−). ROS are highly reactive and excessive mitochondrial production causes oxidative damage to macromolecules, and therefore, counterbalancing is required. The mitochondria rely on the combined activities of glutathione and thioredoxins to decompose the locally generated ROS. Nicotinamide adenine dinucleotide phosphate (NADPH) donates the reducing equivalent for the regeneration of glutathione and thioredoxin, necessary to neutralize (ie, reduce) ROS.
      Figure thumbnail gr3
      Figure 3Mitochondrial generation of ROS and their scavenging by antioxidant defenses
      The mitochondrial reactive oxygen species are formed from the leakage of electrons from the electron transport chain complex I and complex III. O2•− is generated by the addition of an electron to molecular oxygen. O2•− is dismutated into H2O2 by SOD. H2O2 forms hydroxyl radical in the presence of Fe2+ or is reduced to H2O by GPx and TPx in the presence of their reducing equivalents GSH and TRXRed, respectively. The reducing capacity of GPx and Prx is dependent on the supply of NADPH from the pentose phosphate pathway. Complexes I and II require NADH and FADH2 which are supplied by the TCA cycle.
      CoQ, coenzyme Q; Cyt c, cytochrome c; Fe2+, ferrous ion; FADH2, flavin adenine dinucleotide; GPx, glutathione peroxidase; GSH, reduced glutathione; GSSG, oxidized glutathione; H2O, hydrogen dioxide; H2O2, hydrogen peroxide; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; O2•−, superoxide; Prx, peroxiredoxin; SOD, superoxide dismutase; TCA, tricarboxylic acid; TPx, thioredoxin peroxidase; TRXRed, reduced thioredoxin; TRXOx, oxidized thioredoxin.
      Aye. Placental metabolism in preeclampsia. Am J Obstet Gynecol 2022.
      Considering the crucial role of NAD(P)+ and NAD(P)H in managing oxidative stress and providing essential cofactors for metabolic reactions, the maintenance of NAD(P)+ and NAD(P)H balance is critical to cellular homeostasis. Glycolysis consumes NAD+, which can be resupplied by LDH conversion of pyruvate to lactate, with oxidation of NADH in the process. The PPP also produces NADPH, providing the reducing equivalents for the biosynthesis of lipids, cholesterol, and nucleotides. In the mitochondria, the reduction of NAD+ to NADH during isocitrate and α-KG oxidation is resupplied by OXPHOS by complexes I and II that oxidizes NADH to NAD+.
      It is important to consider that although excessive ROS production is undesirable, low ROS concentrations are responsible for a wide variety of physiological processes in the placenta.
      • Burton G.J.
      • Jauniaux E.
      Oxidative stress.
      Therefore, the inappropriate suppression of ROS may have detrimental effects on placental development and function (discussed in the section “Antioxidants to diminish placental oxidative stress”).

      Metabolites in the Control of Cell Signaling and Gene Regulation

      Perturbations in cellular energy metabolism have additional consequences beyond bioenergetics and biosynthesis. This is because energy metabolism intermediates, cofactors, and cosubstrates also function as signaling molecules (Figure 4). The signaling function provides a means of communicating the cellular status among different organelles and allows for metabolic pathways to be integrated to cellular function.
      Figure thumbnail gr4
      Figure 4Signaling functions of metabolic intermediates
      Intermediaries of central energy metabolism have diverse nonmetabolic signaling roles with important effects on placental physiology and disease. Glycolytic intermediates and ATP-to-ADP ratio signal toward the cellular energy and nutrient sensors AMPK and mTOR, respectively. AMPK is a protein kinase that can inhibit protein synthesis by directly phosphorylating and inhibiting translation elongation proteins or by inhibiting mTOR-dependent protein synthesis. mTOR is also a protein kinase that phosphorylates key proteins regulating protein synthesis and amino acid transport in the placenta. Acetyl-CoA and lactate provide rate-limiting substrates for acetylation and lactylation of histones. Lactate also inhibits HDACs. The SIRT class of HDACs requires NAD+ as cofactors. DNA and histone methylation by TET and JMJD are activated by α-ketoglutarate and inhibited by succinate and fumarate. High α-ketoglutarate to succinate or fumarate ratio enhances PHD activity leading to hydroxylation of HIF-1 and HIF-2α leading to its ubiquitination and proteasomal degradation. Low α-ketoglutarate to succinate or fumarate ratio, hypoxia, and ROS inhibit PHDs leading to HIF-1 and HIF-2α stabilization and nuclear translocation where it promotes transcription of their respective target genes.
      Ac, acetyl group; acetyl-CoA, acetyl coenzyme A; ADP, adenosine diphosphate; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; Flt-1, fms-like tyrosine kinase 1; HAT, histone acetyltransferase; HDAC, histone deacetylase; HIF, hypoxia-inducible factor; JMJD, Jumonji C domain–containing histone demethylase; La, lactyl group; Me, methyl group; mTOR, mechanistic target of rapamycin; NAD+, nicotinamide adenine dinucleotide; PHD, prolyl hydroxylase domain; ROS, reactive oxygen species; SIRT, sirtuin; TCA, tricarboxylic acid; TET, ten-eleven translocation; Ub, ubiquitin.
      Aye. Placental metabolism in preeclampsia. Am J Obstet Gynecol 2022.

      Metabolic control of signal transduction

      Cellular ATP levels are directly sensed through the adenosine monophosphate activated protein kinase (AMPK). AMPK plays a key role as a master regulator of energy homeostasis by directly phosphorylating metabolic enzymes or by phosphorylating transcription factors, coactivators, and corepressors. AMPK is activated by an increase in AMP to ATP ratio indicating a decline in energy levels. In turn, AMPK phosphorylates metabolic enzymes to switch on catabolic pathways that generate ATP such as glycolysis and fatty acid β-oxidation. In addition, AMPK represses ATP-consuming processes including protein translation by inhibition of the mechanistic target of rapamycin (mTOR). The mTOR signaling pathway integrates inputs from upstream extracellular growth factor signals and intracellular metabolites to regulate cell growth and metabolism. In the placenta, mTOR activity regulates mitochondrial metabolism and nutrient transfer,
      • Rosario F.J.
      • Kanai Y.
      • Powell T.L.
      • Jansson T.
      Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells.
      • Roos S.
      • Kanai Y.
      • Prasad P.D.
      • Powell T.L.
      • Jansson T.
      Regulation of placental amino acid transporter activity by mammalian target of rapamycin.
      • Rosario F.J.
      • Gupta M.B.
      • Myatt L.
      • et al.
      Mechanistic target of rapamycin complex 1 promotes the expression of genes encoding electron transport chain proteins and stimulates oxidative phosphorylation in primary human trophoblast cells by regulating mitochondrial biogenesis.
      • Gaccioli F.
      • Lager S.
      • Powell T.L.
      • Jansson T.
      Placental transport in response to altered maternal nutrition.
      • Jansson T.
      • Aye I.L.M.H.
      • Goberdhan D.C.I.
      The emerging role of mTORC1 signaling in placental nutrient-sensing.
      and both the activities of mTOR and AMPK are altered in placenta-related pregnancy complications associated with altered fetal growth, including preeclampsia.
      • Yung H.W.
      • Calabrese S.
      • Hynx D.
      • et al.
      Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction.
      ,
      • Roos S.
      • Jansson N.
      • Palmberg I.
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      • Powell T.L.
      • Jansson T.
      Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth.
      • Chen Y.Y.
      • Rosario F.J.
      • Shehab M.A.
      • Powell T.L.
      • Gupta M.B.
      • Jansson T.
      Increased ubiquitination and reduced plasma membrane trafficking of placental amino acid transporter SNAT-2 in human IUGR.
      • Jansson N.
      • Rosario F.J.
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      • et al.
      Activation of placental mTOR signaling and amino acid transporters in obese women giving birth to large babies.
      The glycolytic intermediate DHAP activates mTOR through an AMPK independent route, thus allowing cells to respond to glucose availability in a manner independent of cellular energy status.
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      • Krawczyk P.A.
      • Scaria S.M.
      • et al.
      Dihydroxyacetone phosphate signals glucose availability to mTORC1.

      Transcriptional and epigenetic regulation of gene expression by central energy metabolism

      Hypoxia-inducible factors (HIFs) are well characterized for their role in altering gene transcription to match oxygen demand with availability. Under normoxia, the proline residues of HIF-1 and HIF-2α are hydroxylated by prolyl hydroxylase domain (PHD) proteins. This allows HIFs to be recognized by a ubiquitin ligase targeting them for proteasomal degradation. Under hypoxic conditions, PHD activity is impaired resulting in HIF-1 and HIF-2α accumulation and nuclear translocation where they dimerize with HIF-1β and function as a transcription factor. PHDs are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that catalyze α-KG (also known as 2-oxoglutarate) into succinate and use O2 as a cosubstrate.
      • Kaelin Jr., W.G.
      Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases.
      As with other OGDDs, PHDs are inhibited by succinate and fumarate under normoxic conditions.
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      • Hirsilä M.
      • Remes A.M.
      • Hassinen I.E.
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      Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF.
      Interestingly, mitochondrial ROS can also inhibit PHDs to activate HIF-1 or HIF-2α under normoxia.
      • Chandel N.S.
      • McClintock D.S.
      • Feliciano C.E.
      • et al.
      Reactive oxygen species generated at mitochondrial Complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing.
      ,
      • Guzy R.D.
      • Hoyos B.
      • Robin E.
      • et al.
      Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing.
      Therefore, HIF activity is governed as much by the cellular metabolic state as by the oxygen tension. In the placenta, both HIF-1α and HIF-2α are stabilized under hypoxia
      • Sasagawa T.
      • Nagamatsu T.
      • Morita K.
      • et al.
      HIF-2α, but not HIF-1α, mediates hypoxia-induced up-regulation of Flt-1 gene expression in placental trophoblasts.
      ,
      • Korkes H.A.
      • De Oliveira L.
      • Sass N.
      • Salahuddin S.
      • Karumanchi S.A.
      • Rajakumar A.
      Relationship between hypoxia and downstream pathogenic pathways in preeclampsia.
      but may have different transcriptional targets. HIF-1α regulates glycolytic enzymes in several nonplacental cells.
      • Hu C.J.
      • Wang L.Y.
      • Chodosh L.A.
      • Keith B.
      • Simon M.C.
      Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation.
      HIF-2α promotes sFlt-1 transcription in trophoblast-derived cell lines,
      • Sasagawa T.
      • Nagamatsu T.
      • Morita K.
      • et al.
      HIF-2α, but not HIF-1α, mediates hypoxia-induced up-regulation of Flt-1 gene expression in placental trophoblasts.
      which may explain why levels of sFlt-1 messenger mRNA do not correlate with HIF-1α protein in normal or placentas with preeclampsia.
      • Korkes H.A.
      • De Oliveira L.
      • Sass N.
      • Salahuddin S.
      • Karumanchi S.A.
      • Rajakumar A.
      Relationship between hypoxia and downstream pathogenic pathways in preeclampsia.
      Transcription is intimately associated with a permissive chromatin environment that is facilitated by specific histone modifications. Nearly all chromatin-modifying enzymes rely on substrates and cofactors generated from central energy metabolism. Histone acetylation promotes an open chromatin state and thus gene transcription. Acetyl-CoA is the rate-limiting substrate for histone acetylation, and the regulation of acetyl-CoA metabolism profoundly influences histone acetylation.
      • Lozoya O.A.
      • Wang T.
      • Grenet D.
      • et al.
      Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression.
      • McDonnell E.
      • Crown S.B.
      • Fox D.B.
      • et al.
      Lipids reprogram metabolism to become a major carbon source for histone acetylation.
      • Moussaieff A.
      • Rouleau M.
      • Kitsberg D.
      • et al.
      Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells.
      In the reversal to this process, acetyl groups on histones are removed by histone deacetylases (HDACs). Deacetylation reactions are also metabolically sensitive. Lactate is a weak inhibitor of global HDAC activity,
      • Latham T.
      • MacKay L.
      • Sproul D.
      • et al.
      Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression.
      whereas the sirtuin (SIRT) class of HDACs requires NAD+ as a cofactor.
      • Cantó C.
      • Menzies K.J.
      • Auwerx J.
      NAD(+) metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus.
      Interestingly, lactate also functions as an epigenetic modifier through histone lactylation promoting gene expression.
      • Zhang D.
      • Tang Z.
      • Huang H.
      • et al.
      Metabolic regulation of gene expression by histone lactylation.
      Hence, histone acetylation and lactylation provide a mechanism by which glycolytic and oxidative metabolism intermediates are uncoupled from energy metabolism and function in the regulation of gene expression.
      S-adenosyl methionine (SAM) is a substrate for the methylation of histones and DNA. SAM generation by one-carbon metabolism requires NADPH and serine,
      • Locasale J.W.
      Serine, glycine and one-carbon units: cancer metabolism in full circle.
      ,
      • Yang M.
      • Vousden K.H.
      Serine and one-carbon metabolism in cancer.
      which are intermediates of central energy metabolism. PPP generates NADPH whereas 3-phosphoglycerate channels metabolites into the serine synthesis pathway (Figure 1). Notably, stimulating glycolysis increases SAM production by increasing carbon flux into these pathways.
      • Yu W.
      • Wang Z.
      • Zhang K.
      • et al.
      One-carbon metabolism supports S-adenosylmethionine and histone methylation to drive inflammatory macrophages.
      Similarly, demethylation of histones and DNA is coordinately regulated by the same metabolites. The Jumonji C domain–containing histone demethylases (JMJDs) and ten-eleven translocation DNA demethylases are 2-OGDD enzymes, and as such, they require αKG as a cosubstrate and are inhibited by succinate and fumarate, intermediates downstream in the TCA cycle. Therefore, the balance of TCA cycle reactions can affect the level of DNA and histone methylation and thus influence gene expression.

      Reprogramming of Placental Metabolism During Development

      Although metabolic reprogramming has largely been discussed in the context of pathologic states, it is clear that such reprogramming occurs in physiological settings. This is best appreciated in the context of placental development where metabolic reprogramming reflects changes in the requirements of bioenergy and biosynthetic precursors in response to the changing extracellular environment (eg, histiotrophic to hemotrophic nutrition) and cellular demands (eg, proliferation and differentiation). Owing to the obvious constraints, less is known about the mechanisms underpinning human placental metabolism during early pregnancy (ie, first and second trimesters). However, we may infer these mechanisms based on metabolite and enzyme activity measurements. Early placental development takes place in an environment of low oxygen tension and is supported by secretions from the endometrial gland that are rich in carbohydrates.
      • Burton G.J.
      • Watson A.L.
      • Hempstock J.
      • Skepper J.N.
      • Jauniaux E.
      Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy.
      Glycolysis and HBP and PPP enzyme activities are high in the first trimester,
      • Diamant Y.Z.
      • Mayorek N.
      • Neumann S.
      • Shafrir E.
      Enzymes of glucose and fatty acid metabolism in early and term human placenta.
      suggesting a preference for nonoxidative metabolism. The reliance on these pathways may be necessary to support biosynthetic and signaling functions, and the generation of reducing equivalents NADPH and reduced glutathione (GSH) to protect against ROS-mediated teratogenesis.
      • Burton G.J.
      • Hempstock J.
      • Jauniaux E.
      Oxygen, early embryonic metabolism and free radical-mediated embryopathies.
      Despite the low oxygen tension, this environment should not be considered hypoxic, because hypoxia reflects the metabolic state relating to cellular oxygen availability and demand, rather than oxygen tension per se, which varies considerably among different tissues.
      • Carreau A.
      • El Hafny-Rahbi B.
      • Matejuk A.
      • Grillon C.
      • Kieda C.
      Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia.
      For example, placental ATP-to-ADP ratio, glucose and lactate concentrations, and HIF-signaling do not change across gestation.
      • Cindrova-Davies T.
      • van Patot M.T.
      • Gardner L.
      • Jauniaux E.
      • Burton G.J.
      • Charnock-Jones D.S.
      Energy status and HIF signalling in chorionic villi show no evidence of hypoxic stress during human early placental development.
      With the onset of the uteroplacental circulation, the oxygen tension rises and oxidative metabolism becomes dominant.
      • Holland O.J.
      • Hickey A.J.R.
      • Alvsaker A.
      • et al.
      Changes in mitochondrial respiration in the human placenta over gestation.
      The activities of LDH and TCA cycle enzymes increase
      • Jones C.J.
      • Fox H.
      An ultrahistochemical study of the placental content of respiratory enzymes in normal and prolonged pregnancies.
      ,
      • Scisłowski P.W.
      • Zołnierowicz S.
      • Zelewski L.
      Subcellular distribution of isocitrate dehydrogenase in early and term human placenta.
      to meet the greater biosynthetic requirements associated with the rapid growth of the placenta and the fetus. Interestingly, placental bioenergetics (as determined by OXPHOS activity) does not change substantially between the first trimester and term, despite the >5-fold increase in mitochondrial DNA, suggesting that OXPHOS activity relative to mitochondrial content becomes less efficient.
      • Holland O.J.
      • Hickey A.J.R.
      • Alvsaker A.
      • et al.
      Changes in mitochondrial respiration in the human placenta over gestation.
      It is possible that the considerably larger surface area and higher oxygen concentrations in the term placenta mean that mitochondrial respiration is not required to proceed at full capacity. Indeed, compared with the first-trimester placentas, term placentas have greater spare respiratory capacity
      • Holland O.J.
      • Hickey A.J.R.
      • Alvsaker A.
      • et al.
      Changes in mitochondrial respiration in the human placenta over gestation.
      (defined as the differences between maximal and basal respiration) which may be important for buffering the effects of acute stress such as labor.
      Metabolism is not just a product of developmental programs; metabolic pathways also strongly influence signaling and epigenetic mechanisms associated with development.
      • Miyazawa H.
      • Aulehla A.
      Revisiting the role of metabolism during development.
      ,
      • Gándara L.
      • Wappner P.
      Metabo-devo: a metabolic perspective of development.
      The differentiation of the trophectoderm (from which all trophoblasts are derived) during mouse embryonic development is controlled by glucose metabolism.
      • Chi F.
      • Sharpley M.S.
      • Nagaraj R.
      • Roy SS Sen
      • Banerjee U.
      Glycolysis-independent glucose metabolism distinguishes TE from ICM fate during mammalian embryogenesis.
      However, this process is not associated with its bioenergetic function. Instead, glucose is metabolized into the PPP and HBP to provide nucleotide precursors and glycosylation substrates for posttranslational modification and activation of developmental transcription factors.
      • Chi F.
      • Sharpley M.S.
      • Nagaraj R.
      • Roy SS Sen
      • Banerjee U.
      Glycolysis-independent glucose metabolism distinguishes TE from ICM fate during mammalian embryogenesis.
      In the first-trimester placenta, rapid cytotrophoblast proliferation is required to build a sufficient pool of progenitor cells for syncytiotrophoblast and extravillous trophoblast differentiation. An abundant cytotrophoblast pool may also be necessary to support the development of a durable cytotrophoblast shell that forms a primitive barrier at the maternal-fetal interface.
      • Burton G.J.
      • Jauniaux E.
      The cytotrophoblastic shell and complications of pregnancy.
      Low oxygen tension of the early placental microenvironment has been proposed as a requirement for cytotrophoblast proliferation, whereas differentiation is triggered by the rise in oxygen. However, all 3 trophoblast types are present in the placenta before the onset of uteroplacental circulation and thus the surge in oxygen. Moreover, studies using human cytotrophoblast stem cells and organoid models demonstrate continuous self-renewal under atmospheric oxygen concentrations.
      • Okae H.
      • Toh H.
      • Sato T.
      • et al.
      Derivation of human trophoblast stem cells.
      • Haider S.
      • Meinhardt G.
      • Saleh L.
      • et al.
      Self-renewing trophoblast organoids recapitulate the developmental program of the early human placenta.
      • Turco M.Y.
      • Gardner L.
      • Kay R.G.
      • et al.
      Trophoblast organoids as a model for maternal–fetal interactions during human placentation.
      We propose an alternative hypothesis whereby the metabolic state, rather than oxygen per se, regulates trophoblast fate. A common characteristic of progenitor cells (including cytotrophoblasts) is that they require high levels of histone acetylation to maintain an open chromatin state, whereas differentiation is associated with a rapid decline in global histone acetylation.
      • Miyazawa H.
      • Aulehla A.
      Revisiting the role of metabolism during development.
      ,
      • Mathieu J.
      • Ruohola-Baker H.
      Metabolic remodeling during the loss and acquisition of pluripotency.
      The metabolic support for histone acetylation is achieved through high glycolytic activity generating pyruvate and subsequent oxidation into acetyl-CoA. At the same time, consumption of NAD+ during glycolysis reduces NAD+-dependent HDAC activity, thus also favoring histone acetylation. Consistent with this hypothesis, cytotrophoblasts exhibit higher glycolytic metabolism than their differentiated syncytiotrophoblasts,
      • Kolahi K.S.
      • Valent A.M.
      • Thornburg K.L.
      Cytotrophoblast, not syncytiotrophoblast, dominates glycolysis and oxidative phosphorylation in human term placenta.
      and higher histone acetylation levels.
      • Jaju Bhattad G.
      • Jeyarajah M.J.
      • McGill M.G.
      • et al.
      Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts.
      Moreover, the loss of the HDAC SIRT1 in mice results in trophoblast differentiation failure and reduced fetal and placental weights.
      • Jaju Bhattad G.
      • Jeyarajah M.J.
      • McGill M.G.
      • et al.
      Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts.

      Dysregulation of Metabolic Reprogramming in Preeclampsia

      Because metabolic reprogramming is a necessary component of physiology, the inability of the placenta to alter its metabolism to the changing environment may underlie abnormal placental development and dysfunction. Derangements in energy metabolism and its consequences are commonly reported in the placentas of women with preeclampsia. However, the various subtypes of preeclampsia show differences in their ability or inability to reprogram their metabolism (Figure 5). Mitochondrial dysfunction and oxidative stress are commonly reported in placentas with preeclampsia of various subtypes.
      • Roberts J.M.
      • Escudero C.
      The placenta in preeclampsia.
      ,
      • Marín R.
      • Chiarello D.I.
      • Abad C.
      • Rojas D.
      • Toledo F.
      • Sobrevia L.
      Oxidative stress and mitochondrial dysfunction in early-onset and late-onset preeclampsia.
      It is still unclear whether mitochondrial dysfunction is the cause of oxidative stress or vice versa, but these 2 events are likely interrelated and may compound each other. Interestingly, women with known pathogenic mitochondrial DNA mutations entering pregnancy are highly likely to develop preeclampsia.
      • Say R.E.
      • Whittaker R.G.
      • Turnbull H.E.
      • McFarland R.
      • Taylor R.W.
      • Turnbull D.M.
      Mitochondrial disease in pregnancy: a systematic review.
      ,
      • Torbergsen T.
      • Oian P.
      • Mathiesen E.
      • Borud O.
      Pre-eclampsia--a mitochondrial disease?.
      Although these cases are very rare, such “experiments of nature” underline the importance of mitochondria in the development of preeclampsia.
      Figure thumbnail gr5
      Figure 5Placental metabolic reprogramming during development and adaptation to preeclampsia
      First-trimester placentas use glycolysis and its shunt pathways to generate bioenergy and biosynthetic precursors, although they do retain some mitochondrial activity. Mild preeclampsia resulting in term delivery may allow the placenta to adapt to mitochondrial dysfunction by reverting its metabolism to the early developmental state. Failure in metabolic reprogramming may result in the loss of bioenergetic and biosynthetic homeostasis resulting in the severe form of preeclampsia associated with preterm delivery and fetal growth restriction. Solid arrows indicate changes previously reported in literature, and dashed arrows indicate predicted effects.
      α-KG, α-ketoglutarate; acetyl-CoA, acetyl coenzyme A; ADP, adenosine diphosphate; ATP, adenosine triphosphate; Glu, glutamine; NAD+, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; ROS, reactive oxygen species; TCA, tricarboxylic acid.
      Aye. Placental metabolism in preeclampsia. Am J Obstet Gynecol 2022.
      ROS are triggered by hypoxia and reoxygenation associated with intermittent placental perfusion secondary to abnormally shallow invasion.
      • Hung T.H.
      • Skepper J.N.
      • Charnock-Jones D.S.
      • Burton G.J.
      Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia.
      ,
      • Hung T.H.
      • Burton G.J.
      Hypoxia and reoxygenation: a possible mechanism for placental oxidative stress in preeclampsia.
      Paradoxically, prolonged hypoxia without reoxygenation also promotes mitochondrial ROS generation. This occurs because insufficient oxygen is available for reduction by the ETC and the reducing equivalents NADH and FADH2 accumulate, increasing the availability of electrons for the reduction of oxygen to O2•− and subsequently into H2O2. Hypoxia and mitochondria-generated ROS stabilize both HIF-1 and HIF-2α.
      • Guzy R.D.
      • Hoyos B.
      • Robin E.
      • et al.
      Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing.
      This leads to the transcription of glycolytic enzymes through HIF-1α
      • Fukasawa M.
      • Tsuchiya T.
      • Takayama E.
      • et al.
      Identification and characterization of the hypoxia-responsive element of the human placental 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene.
      whereas HIF-2α increases antiangiogenic factors including sFlt-1 to be released from the trophoblasts into the maternal circulation leading to maternal endothelial activation.
      • Sasagawa T.
      • Nagamatsu T.
      • Morita K.
      • et al.
      HIF-2α, but not HIF-1α, mediates hypoxia-induced up-regulation of Flt-1 gene expression in placental trophoblasts.
      ,
      • Clark D.E.
      • Smith S.K.
      • He Y.
      • et al.
      A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation.
      Varying degrees of mitochondrial dysfunction have been reported in different preeclampsia subtypes and may be proposed as the initial stimulus for altered energy metabolism. However, the degree of alterations or inability to adapt sufficiently in energy metabolism may exacerbate the disease. In less severe forms of preeclampsia associated with term delivery, mitochondrial function adapts by upregulating OXPHOS and antioxidant activity.
      • Holland O.J.
      • Cuffe J.S.M.
      • Dekker Nitert M.
      • et al.
      Placental mitochondrial adaptations in preeclampsia associated with progression to term delivery.
      Failure to adapt may result in mitochondrial dysfunction placing greater reliance on glycolysis to maintain the bioenergetic requirements but may lead to reduced net ATP production owing to the lower efficiency of glycolysis. This can also result in greater flux into the HBP
      • Gómez-Gutiérrez A.M.
      • Parra-Sosa B.E.
      • Bueno-Sánchez J.C.
      Glycosylation profile of the transferrin receptor in gestational iron deficiency and early-onset severe preeclampsia.
      ,
      • Marini M.
      • Bonaccini L.
      • Thyrion G.D.Z.
      • Vichi D.
      • Parretti E.
      • Sgambati E.
      Distribution of sugar residues in human placentas from pregnancies complicated by hypertensive disorders.
      which promotes cell survival through UDP-glcNAc–dependent glycosylation and inhibition of apoptotic proteins.
      • Akella N.M.
      • Ciraku L.
      • Reginato M.J.
      Fueling the fire: emerging role of the hexosamine biosynthetic pathway in cancer.
      In severe preeclampsia associated with preterm delivery and FGR, glycolytic function is also impaired, suggesting a failure in reprogramming of metabolism. In these placentas, glycolytic enzyme activities are decreased resulting in lower production of pyruvate and lactate,
      • Bloxam D.L.
      • Bullen B.E.
      • Walters B.N.J.
      • Lao T.T.
      Placental glycolysis and energy metabolism in preeclampsia.
      the latter of which provides fuel for fetal oxidation. Anaplerotic flux into the TCA cycle via the placental-fetal glutamine-glutamate shuttle is also dysregulated in FGR-associated placentas,
      • McIntyre K.R.
      • Vincent K.M.M.
      • Hayward C.E.
      • et al.
      Human placental uptake of glutamine and glutamate is reduced in fetal growth restriction.
      which would affect the fetal amino acid supply and the provision of biosynthetic precursors and bioenergetic functions in the placenta. The ensuing decline in placental ATP levels activates AMPK that functions to restore energy balance by reducing ATP-demanding processes including placental nutrient transport and protein synthesis via mTOR inhibition, contributing to placenta-related FGR.
      • Jansson T.
      • Aye I.L.M.H.
      • Goberdhan D.C.I.
      The emerging role of mTORC1 signaling in placental nutrient-sensing.
      Protein synthesis occurs in the ER, which consumes large amounts of ATP imported from the cytosol and the mitochondria. Considerable cross-talk between the mitochondria and the ER membranes exists via direct contact sites called mitochondrial associated membranes (MAMs) to signal cellular metabolic status and stress. For example, to meet the energy demands for protein synthesis, calcium signaling by the MAM stimulates TCA cycle enzymes leading to enhanced ATP production via OXPHOS.
      • Hayashi T.
      • Rizzuto R.
      • Hajnoczky G.
      • Su T.P.
      MAM: more than just a housekeeper.
      Severe preeclampsia is associated with ER stress
      • Yung H.W.
      • Colleoni F.
      • Dommett E.
      • et al.
      Noncanonical mitochondrial unfolded protein response impairs placental oxidative phosphorylation in early-onset preeclampsia.
      which decreases protein synthesis to reduce the demand for ATP.
      • Yung H.W.
      • Calabrese S.
      • Hynx D.
      • et al.
      Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction.
      Moreover, the ER stress–mediated transcription factor XBP-1s increases the transcription of HBP enzyme to promote cell survival,
      • Wang Z.V.
      • Deng Y.
      • Gao N.
      • et al.
      Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway.
      suggesting that ER stress response may support metabolic reprogramming toward glycolysis. An additional consequence of altered energy metabolism relates to its epigenetic functions. Reductions in trophoblast acetyl-CoA synthesis or NAD+ homeostasis may lead to reduced cytotrophoblast proliferation leading to the incomplete development of the cytotrophoblastic shell and a reduction in the source of extravillous trophoblasts for adequate trophoblast invasion. Indeed, a single-cell transcriptomic study indicated altered extravillous trophoblast transcript signatures in placentas with preeclampsia suggesting differentiation defects.
      • Tsang J.C.H.
      • Vong J.S.L.
      • Ji L.
      • et al.
      Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics.
      However, the mechanistic relationship between metabolism and trophoblast differentiation in preeclampsia remains to be investigated.
      Collectively, these studies suggest that impaired placental energy metabolism in preeclampsia may have widespread effects on cellular processes beyond ATP production and may lead to alterations in biosynthetic precursors, oxidative stress, and transcriptional and epigenetic modifications.

      Sex Differences in Placental Metabolism May Underlie Preeclampsia Severity

      Fetal sex differences are increasingly recognized as an important determinant of the incidence and outcome in placenta-related pregnancy complications.
      • Broere-Brown Z.A.
      • Adank M.C.
      • Benschop L.
      • et al.
      Fetal sex and maternal pregnancy outcomes: a systematic review and meta-analysis.
      • Walker M.G.
      • Fitzgerald B.
      • Keating S.
      • Ray J.G.
      • Windrim R.
      • Kingdom J.C.P.
      Sex-specific basis of severe placental dysfunction leading to extreme preterm delivery.
      • Jaskolka D.
      • Retnakaran R.
      • Zinman B.
      • Kramer C.K.
      Fetal sex and maternal risk of pre-eclampsia/eclampsia: a systematic review and meta-analysis.
      Overall, preeclampsia risk is higher in male fetuses. However, when stratified by subtype, term preeclampsia was associated with male fetus whereas preterm preeclampsia is more common when the fetus was female.
      • Broere-Brown Z.A.
      • Adank M.C.
      • Benschop L.
      • et al.
      Fetal sex and maternal pregnancy outcomes: a systematic review and meta-analysis.
      ,
      • Schalekamp-Timmermans S.
      • Arends L.R.
      • et al.
      Global Pregnancy Collaboration
      Fetal sex-specific differences in gestational age at delivery in pre-eclampsia: a meta-analysis.
      One hypothesis that has been proposed to explain these differences relates to early placental development.
      • Myatt L.
      • Muralimanoharan S.
      • Maloyan A.
      Effect of preeclampsia on placental function: influence of sexual dimorphism, microRNA’s and mitochondria.
      Male embryos are more susceptible to suboptimal implantation and abnormal placental development.
      • Murji A.
      • Proctor L.K.
      • Paterson A.D.
      • Chitayat D.
      • Weksberg R.
      • Kingdom J.
      Male sex bias in placental dysfunction.
      Therefore, pregnancies with a male embryo that are susceptible to develop preeclampsia owing to impaired placentation may already have miscarried in the first trimester. This is consistent with the higher rates of first-trimester miscarriage in male embryos.
      • Orzack S.H.
      • Stubblefield J.W.
      • Akmaev V.R.
      • et al.
      The human sex ratio from conception to birth.
      In those pregnancies with preeclampsia that proceed past the first trimester, the male placentas consistently show greater pathologic features such as inflammatory and oxidative stress.
      • Myatt L.
      • Muralimanoharan S.
      • Maloyan A.
      Effect of preeclampsia on placental function: influence of sexual dimorphism, microRNA’s and mitochondria.
      ,
      • Muralimanoharan S.
      • Maloyan A.
      • Myatt L.
      Evidence of sexual dimorphism in the placental function with severe preeclampsia.
      Fetal sex differences in placental metabolism may underlie some of the effects of preeclampsia pathophysiology. Placental sex–dependent alterations in oxidative metabolism have been reported in several pregnancy complications including preeclampsia.
      • Muralimanoharan S.
      • Maloyan A.
      • Myatt L.
      Evidence of sexual dimorphism in the placental function with severe preeclampsia.
      • Muralimanoharan S.
      • Guo C.
      • Myatt L.
      • Maloyan A.
      Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity.
      • Wang Y.
      • Bucher M.
      • Myatt L.
      Use of glucose, glutamine, and fatty acids for trophoblast respiration in lean, obese, and gestational diabetic women.
      These studies indicate that the male placenta demonstrates a lower capacity to reprogram their metabolism in response to changes in nutrient source or stress stimuli.
      The human placental transcriptome exhibits profound sex differences throughout gestation.
      • Sood R.
      • Zehnder J.L.
      • Druzin M.L.
      • Brown P.O.
      Gene expression patterns in human placenta.
      • Buckberry S.
      • Bianco-Miotto T.
      • Bent S.J.
      • Dekker G.A.
      • Roberts C.T.
      Integrative transcriptome meta-analysis reveals widespread sex-biased gene expression at the human fetal-maternal interface.
      • Gonzalez T.L.
      • Sun T.
      • Koeppel A.F.
      • et al.
      Sex differences in the late first trimester human placenta transcriptome.
      • Syrett C.M.
      • Sierra I.
      • Berry C.L.
      • Beiting D.
      • Anguera M.C.
      Sex-specific gene expression differences are evident in human embryonic stem cells and during in vitro differentiation of human placental progenitor cells.
      • Gong S.
      • Sovio U.
      • Aye I.L.
      • et al.
      Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia.
      These sex differences may be explained by genes that escape X chromosome inactivation (XCI) resulting in female-biased expression or overexpression.
      • Balaton B.P.
      • Brown C.J.
      Escape artists of the X chromosome.
      ,
      • Tukiainen T.
      • Villani A.C.
      • Yen A.
      • et al.
      Landscape of X chromosome inactivation across human tissues.
      In term placentas, approximately 15% of the XCI escapees are involved in metabolism.
      • Gong S.
      • Sovio U.
      • Aye I.L.
      • et al.
      Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia.
      One of these escapees, spermine synthase (SMS), participates in polyamine metabolism that is dysregulated in preeclampsia.
      • Gong S.
      • Sovio U.
      • Aye I.L.
      • et al.
      Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia.
      Although polyamine metabolism is not directly associated with energy metabolism, our preliminary findings show that polyamine metabolites strongly correlate with TCA cycle intermediates in the placenta.
      • Aye I.
      • Gong S.
      • Charnock-Jones D.S.
      • Smith G.C.S.
      O-145 spermine synthase (SMS), a placenta specific X chromosome inactivation (XCI) escapee, mediates sex-differences in placental mitochondrial function [abstract].
      Moreover, polyamine depletion decreased both glycolytic and oxidative metabolism resulting in reduced TCA cycle intermediates and OXPHOS activity,
      • Aye I.
      • Gong S.
      • Charnock-Jones D.S.
      • Smith G.C.S.
      O-145 spermine synthase (SMS), a placenta specific X chromosome inactivation (XCI) escapee, mediates sex-differences in placental mitochondrial function [abstract].
      which recapitulates the metabolic phenotypes of placental dysfunction in severe preeclampsia.
      • Bloxam D.L.
      • Bullen B.E.
      • Walters B.N.J.
      • Lao T.T.
      Placental glycolysis and energy metabolism in preeclampsia.
      Importantly, female trophoblasts were resistant to polyamine depletion owing to the higher SMS expression associated with XCI escape. Moreover, the decrease in glycolysis and oxidative metabolism with polyamine depletion led to reduced acetyl-CoA availability and decreased histone acetylation resulting in widespread changes in gene expression.
      • Avellino G.
      • Charnock-Jones D.S.
      • Smith G.
      • Aye I.L.
      O-004 placental central carbon metabolism links polyamines to histone acetylation [abstract].
      These findings suggest that fetal sex differences in placental metabolism have far-reaching effects beyond bioenergetics and affect epigenetic regulation of placental function.

      Placental Energy Metabolism as a Target for the Treatment of Preeclampsia

      There is no universally accepted treatment for preeclampsia. The current standard of care is aimed at resolving the maternal symptoms, and delivery remains the only cure. Given the central role of the placenta in preeclampsia pathophysiology, treatments aimed at resolving placental dysfunction are warranted. We briefly review the role of antioxidants and metformin as therapeutic strategies for the prevention or treatment of preeclampsia and examine their potential implications on placental energy metabolism and provide possible explanations for their effectiveness.

      Antioxidants to diminish placental oxidative stress

      Based on the evidence that preeclampsia is commonly associated with maternal and placental oxidative stress, several clinical studies have examined the effectiveness of antioxidants, and in particular vitamins C and E, to prevent or ameliorate the course of preeclampsia. Vitamins C and E are readily available over-the-counter supplements with potent antioxidant properties. Vitamin C is a water-soluble antioxidant that scavenges free radicals, whereas vitamin E is a lipid-soluble peroxyl radical scavenger.
      • Traber M.G.
      • Stevens J.F.
      Vitamins C and E: beneficial effects from a mechanistic perspective.
      Therefore, the combined use of vitamins C and E offers protection against multiple forms of ROS.
      The initial clinical trials of vitamins C and E supplementation beginning at midpregnancy in women at risk of preeclampsia suggested improved oxidative stress markers
      • Chappell L.C.
      • Seed P.T.
      • Briley A.
      • et al.
      A longitudinal study of biochemical variables in women at risk of preeclampsia.
      ,
      • Chappell L.C.
      • Seed P.T.
      • Kelly F.J.
      • et al.
      Vitamin C and E supplementation in women at risk of preeclampsia is associated with changes in indices of oxidative stress and placental function.
      and clinical outcomes.
      • Chappell L.C.
      • Seed P.T.
      • Briley A.L.
      • et al.
      Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial.
      However, larger clinical trials and several meta-analyses failed to show any benefits and even demonstrated some harm including reduced fetal growth, preterm birth, and stillbirth.
      • Chappell L.C.
      • Seed P.T.
      • Briley A.L.
      • et al.
      Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial.
      • Rahimi R.
      • Nikfar S.
      • Rezaie A.
      • Abdollahi M.
      A meta-analysis on the efficacy and safety of combined vitamin C and e supplementation in preeclamptic women.
      • Poston L.
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      • Conde-Agudelo A.
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      • Rumbold A.
      • Ota E.
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      Vitamin E supplementation in pregnancy.
      Taken together, these trials and several other studies
      • Palacios C.
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      Vitamin D supplementation for women during pregnancy.
      ,
      • Ota E.
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      • Middleton P.
      • et al.
      Zinc supplementation for improving pregnancy and infant outcome.
      targeting oxidative stress have failed to improve preeclampsia outcome. The exact reasons and mechanisms as to why these studies have failed to produce the expected beneficial effects remain largely unknown but several explanations can be posited. These include the failure to translate the beneficial in vitro effects to in vivo findings owing to poor bioavailability and pharmacokinetic profiles, heterogeneity in the types of antioxidants and doses, and the lack of an appropriate preclinical animal model for preeclampsia. The discrepancies may also be caused by the possibility that oxidative stress represents 1 endpoint in a cascade of events related to placental metabolic dysfunction, and therefore, targeting oxidative stress alone is unlikely to produce substantial overall benefits. It is also interesting to note that in addition to pregnancy disorders, antioxidant supplementation has failed to deliver the expected benefits for many other diseases unrelated to pregnancy and may even increase mortality.
      • Bjelakovic G.
      • Nikolova D.
      • Gluud L.L.
      • Simonetti R.G.
      • Gluud C.
      Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.
      The evidence for antioxidants to cause harm reinforces the notion that ROS play an important physiological role during pregnancy and that undue suppression of ROS may have detrimental effects. This was elegantly demonstrated in mice where experimental induction of a master transcriptional regulator of the cellular antioxidant system paradoxically led to adverse pregnancy outcomes.
      • Nezu M.
      • Souma T.
      • Yu L.
      • et al.
      Nrf2 inactivation enhances placental angiogenesis in a preeclampsia mouse model and improves maternal and fetal outcomes.
      Nuclear factor erythroid 2–related factor 2 (Nrf2) is a transcription factor that is activated in response to oxidative stress. Its activity is suppressed under basal conditions by the binding of Kelch-like ECH–associated protein 1 (KEAP1) which facilitates Nrf2 degradation in the proteasome.
      • Ma Q.
      Role of Nrf2 in oxidative stress and toxicity.
      However, on exposure to ROS, KEAP1 is oxidized which causes Nrf2 release into the nucleus where it binds to antioxidant response elements in promoter regions of numerous antioxidant genes initiating their transcription. Hence, knockout of Nrf2 in mice does not produce any obvious phenotypes. However, genetic or pharmacologic induction of Nrf2 in a mouse preeclampsia model worsened FGR and decreased placental size, despite reductions in oxidative damage. Similarly, human placental trophoblasts and explants treated with pharmacologically relevant concentrations of vitamin C or E demonstrate higher apoptosis even though oxidative stress was improved.
      • Kawashima A.
      • Sekizawa A.
      • Koide K.
      • et al.
      Vitamin C induces the reduction of oxidative stress and paradoxically stimulates the apoptotic gene expression in extravillous trophoblasts derived from first-trimester tissue.
      ,
      • Hung T.H.
      • Chen S.F.
      • Li M.J.
      • Yeh Y.L.
      • Hsieh T.T.
      Differential effects of concomitant use of vitamins C and E on trophoblast apoptosis and autophagy between normoxia and hypoxia-reoxygenation.
      Clearly, targeting of ROS remains an important therapeutic strategy but this needs to be finely balanced to avoid inhibiting the low physiological concentrations of ROS that are required for physiological functions.

      Metformin targets multiple pathways of placental energy metabolism

      Metformin is commonly prescribed for the management of type 2 diabetes mellitus primarily owing to its effects in reducing hepatic glucose production. The precise mechanism of action of metformin remains unclear because it has been associated with pleiotropic effects in different tissues and has been proposed to have many beneficial effects. As such, more than 1700 clinical trials have been registered to test the effects of metformin in different diseases (https://clinicaltrials.gov). Owing to its antihyperglycemic and insulin-sensitizing effects, metformin is prescribed during pregnancy for the treatment of pregestational type 2 diabetes mellitus, gestational diabetes, and polycystic ovarian syndrome.
      • Nguyen L.
      • Chan S.Y.
      • Teo A.K.K.
      Metformin from mother to unborn child—are there unwarranted effects?.
      In a randomized control trial examining the effects of metformin compared with placebo in nondiabetic obese women, metformin had no effect on the primary outcome (birthweight) but reduced preeclampsia incidence by more than 3-fold,
      • Syngelaki A.
      • Nicolaides K.H.
      • Balani J.
      • et al.
      Metformin versus placebo in obese pregnant women without diabetes mellitus.
      thus prompting subsequent studies investigating its effectiveness for preeclampsia. However, meta-analyses of metformin have raised the concern that it may increase the risk of small-for-gestational-age infants
      • Tarry-Adkins J.L.
      • Aiken C.E.
      • Ozanne S.E.
      Comparative impact of pharmacological treatments for gestational diabetes on neonatal anthropometry independent of maternal glycaemic control: a systematic review and meta-analysis.
      ,
      • Tarry-Adkins J.L.
      • Aiken C.E.
      • Ozanne S.E.
      Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: a systematic review and meta-analysis.
      compared with other glucose-normalizing therapeutic approaches.
      Metformin has profound effects on cellular energy metabolism that may explain some of the observed effects on the placenta with preeclampsia (Figure 6). Metformin inhibits complex I activity resulting in reduced OXPHOS but decreases mitochondrial ROS generation in the process. Complex I inhibition also prevents NADH oxidation decreasing the availability of essential cofactors required to run the TCA cycle.
      • Liu X.
      • Romero I.L.
      • Litchfield L.M.
      • Lengyel E.
      • Locasale J.W.
      Metformin targets central carbon metabolism and reveals mitochondrial requirements in human cancers.
      The decrease in the TCA cycle metabolite α-KG may explain the decrease in HIF-2α stabilization by PHDs in metformin-treated primary trophoblasts and suppression of sFlt-1 and soluble endoglin secretion, lessening the impact of placental stress–mediated endothelial dysfunction.
      • Brownfoot F.C.
      • Hastie R.
      • Hannan N.J.
      • et al.
      Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction.
      The reduction in α-KG by metformin will also inhibit other 2-OGDD enzymes including JMJDs.
      • Tanaka Y.
      • Konishi A.
      • Obinata H.
      • Tsuneoka M.
      Metformin activates KDM2A to reduce rRNA transcription and cell proliferation by dual regulation of AMPK activity and intracellular succinate level.
      The decline in ATP as a result of reduced OXPHOS activity leads to AMPK activation.
      • Shaw R.J.
      • Lamia K.A.
      • Vasquez D.
      The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin.
      In placentas with preeclampsia, AMPK activation by metformin may have beneficial adaptive effects by removing damaged mitochondria by mitophagy. Moreover, AMPK activates peroxisome proliferator–activated receptor gamma coactivator 1-alpha (PGC-1α),
      • Garcia D.
      • Shaw R.J.
      AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance.
      which functions as a transcription coactivator that interacts with a range of transcription factors. PGC-1α plays a prominent role in regulating the transcription of nuclear-encoded mitochondrial proteins promoting mitochondrial biogenesis. Therefore, AMPK activation by metformin may have dual effects on the mitochondria by removing damaged mitochondria concomitant with mitochondrial biogenesis to restore mitochondrial function.
      Figure thumbnail gr6
      Figure 6Metformin targets multiple pathways in energy metabolism
      The key metabolic effects of metformin are a result of complex I inhibition and activation of AMPK. The detailed description of the potential effects is described in the main text. In summary, the outcomes include reduction in mitochondrial ROS generation; rerouting of metabolism toward glycolysis; restoring mitochondrial biogenesis and inhibition of 2-oxoglutarate dependent dioxygenases such as TET, JMJD, and PHD; and activation of AMPK and its downstream effects.
      ADP, adenosine diphosphate; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; CoQ, coenzyme Q; Cyt c, cytochrome c; G6Pase, glucose 6-phosphatase; HIF, hypoxia-inducible factor; HK, hexokinase; JMJD, Jumonji C domain–containing histone demethylase; PFK2, phosphofructokinase 2; PGC1α, peroxisome proliferator–activated receptor gamma coactivator 1-alpha; PHD, prolyl hydroxylase domain; ROS, reactive oxygen species; sFlt-1, soluble fms-like tyrosine kinase 1; TCA, tricarboxylic acid; TET, ten-eleven translocation; Ub, ubiquitin.
      Aye. Placental metabolism in preeclampsia. Am J Obstet Gynecol 2022.
      Metformin reroutes metabolic flux into glycolytic pathways through AMPK-dependent and independent mechanisms. AMPK activation stimulates glycolysis by phosphorylating and activating phosphofructokinase
      • Marsin A.S.
      • Bertrand L.
      • Rider M.H.
      • et al.
      Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia.
      and promoting hexokinase II transcription.
      • Thomson D.M.
      • Herway S.T.
      • Fillmore N.
      • et al.
      AMP-activated protein kinase phosphorylates transcription factors of the CREB family.
      Independently of AMPK, metformin inhibits gluconeogenesis by inhibiting glucose 6-phosphatase–mediated conversion of glucose 6-phosphate to glucose.
      • Moonira T.
      • Chachra S.S.
      • Ford B.E.
      • et al.
      Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation.
      Given that gluconeogenesis and glycolysis are regulated in a reciprocal manner to prevent concurrent activity of the opposing pathways, metformin inhibition of glucose 6-phosphatase further supports glycolytic activity. The subsequent increase in glucose 6-phosphate and fructose 6-phosphate may also promote flux into the PPP and the HBP, respectively. These putative effects of metformin are consistent with our preliminary findings in primary human trophoblasts, where metformin treatment at concentrations typically achieved in pregnant women reprogrammed metabolism from OXPHOS toward glycolysis (unpublished data). Although metformin reduces mitochondrial ATP production in normal placentas, in placentas with preeclampsia where mitochondrial dysfunction is prevalent, this effect of metformin may be advantageous because it promotes the reliance on glycolysis over mitochondrial metabolism to restore energy homeostasis and supporting survival through increased flux into the PPP and the HBP.
      The use of metformin in pregnancy is not without risks. Metformin crosses the placenta and metformin treatment is associated with reduced birthweight,
      • Tarry-Adkins J.L.
      • Aiken C.E.
      • Ozanne S.E.
      Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: a systematic review and meta-analysis.
      although it is currently unclear whether these effects are mediated directly through placental or fetal shifts in cellular energy metabolism or indirectly via alterations in fetal glucose homeostasis. In the placenta, AMPK activation by metformin may inhibit mTOR-mediated nutrient transport and protein synthesis. Fetal exposure to metformin could lead to reductions in TCA cycle intermediates such as citrate which are substrates for lipogenesis and biomass production
      • Griss T.
      • Vincent E.E.
      • Egnatchik R.
      • et al.
      Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis.
      contributing to the small-for-gestational-age phenotype.
      Recent studies suggest that metformin mediates additional metabolic effects independent of glucose homeostasis through increased levels of the hormone growth/differentiation factor 15 (GDF15).
      • Coll A.P.
      • Chen M.
      • Taskar P.
      • et al.
      GDF15 mediates the effects of metformin on body weight and energy balance.
      ,
      • Day E.A.
      • Ford R.J.
      • Smith B.K.
      • et al.
      Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss.
      The placenta exhibits the highest tissue levels of GDF15 and secretes large amounts into the maternal circulation.
      • Moore A.G.
      • Brown D.A.
      • Fairlie W.D.
      • et al.
      The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women 1.
      The physiological significance of placental GDF15 secretion is currently unclear, although it is interesting to note that preeclampsia is associated with a decline in maternal serum GDF15 levels.
      • Chen Q.
      • Wang Y.
      • Zhao M.
      • Hyett J.
      • da Silva Costa F.
      • Nie G.
      Serum levels of GDF15 are reduced in preeclampsia and the reduction is more profound in late-onset than early-onset cases.
      Future studies investigating the role of GDF15 in the placenta and the effects of metformin may reveal novel insights into placental metabolic dysfunction.

      Conclusions

      It is now evident that metabolism is much more than a “housekeeping” process and fulfills regulatory roles in physiology. However, a major future task will be to establish clear causal relationships between metabolism and placental developmental programs and to determine whether these links are misaligned during placenta-related pregnancy complications including preeclampsia.
      Reprogramming of energy metabolism is a hallmark of placental development but may also underpin the ability to respond to the pathophysiology underlying preeclampsia. For instance, placental mitochondrial dysfunction is a common observation in preeclampsia but the inability to up-regulate glycolysis is associated with increased severity. It is currently unclear what factors influence placental metabolic flexibility and stress response, but emerging evidence suggests that fetal sex may play an important role. Future therapies aimed at altering energy metabolism may provide an alternative or add-on strategies for the treatment of the placenta with preeclampsia. However, given the multiple phenotypes associated with targeting energy metabolism, the potential risks must be carefully weighed.
      • 1.
        Anaplerosis: Metabolic pathways that result in the replenishing of metabolic intermediates (especially tricarboxylic acid cycle intermediates) to replace those metabolites that have been extracted for biosynthetic processes. The reverse process, that is, the removal of metabolic intermediates from a metabolic cycle, is referred to as cataplerosis.
      • 2.
        Bioenergetic metabolism: Cellular processes that lead to the transformation of nutrients (eg, glucose, amino acids, and fatty acids) into energy-rich metabolites, usually in the form of ATP. In this review, bioenergetic metabolism refers collectively to the metabolic pathways, glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation.
      • 3.
        Biosynthetic processes: Cellular processes by which substrates are converted into more complex macromolecules such as proteins, lipids, and nucleotides, which can be used for building cellular organelles and biomass.
      • 4.
        Central carbon metabolism: A series of metabolic pathways that result in the flow of carbon atoms from nutrients into pathways generating reducing equivalents for energy production and biosynthetic precursors. In eukaryotes, this refers to glycolysis, tricarboxylic acid cycle, and the pentose phosphate pathway.
      • 5.
        Glycolysis: Metabolic pathway that converts glucose into pyruvate or lactate. The true end product of glycolysis (ie, pyruvate or lactate) is currently a matter of debate.
      • 6.
        Hexosamine biosynthetic pathway: A metabolic pathway that operates in parallel to glycolysis and results in the production of uridine diphosphate N-acetylglucosamine, a key substrate for protein glycosylation reactions.
      • 7.
        Metabolic reprogramming: Refers to the ability of cells to alter their metabolism allowing them to adapt to changing internal and environmental conditions. It is important to note that metabolic reprogramming occurs under normal physiological and pathologic conditions.
      • 8.
        Pentose phosphate pathway: A metabolic pathway that operates in parallel to glycolysis that results in the generation of pentoses (5-carbon sugars) and ribose 5-phosphate (a precursor for nucleotide synthesis) and produces NADPH.
      • 9.
        Redox: An oxidation-reduction (redox) reaction involves the transfer of electrons between 2 species. Reducing equivalents and oxidizing agents play important roles as cofactors for numerous enzymes involved in energy metabolism and epigenetics. An imbalance in the redox state may result in oxidative stress.
      • 10.
        TCA cycle: Tricarboxylic acid cycle (also known as the citric acid cycle or Krebs cycle) is a series of chemical reactions that result in the release of stored energy through the oxidation of acetyl-CoA derived from glucose, amino acids, and fatty acids. The TCA cycle is both a major bioenergetic and a biosynthetic pathway. As a bioenergetic pathway, the TCA cycle generates reduced coenzymes (NADH and FADH2) that are used in the electron transport chain for ATP synthesis. As a biosynthetic pathway, the TCA cycle intermediates can be used in the biosynthesis of macromolecules.
      • 11.
        XCI and XCI escape: X chromosome inactivation (XCI) is a process whereby 1 of the 2 X chromosomes is silenced to balance gene dosage between XX females and XY males. XCI escape genes are specific genes that escape XCI silencing resulting in the expression from the inactivated X chromosome. XCI escape can result in female-biased (ie, increased) gene expression.

      Acknowledgments

      Irving L. M. H. Aye is funded by a Next Generation Fellowship from the Centre for Trophoblast Research, University of Cambridge, United Kingdom. We are grateful to Francesca Gaccioli for her valuable comments. All figures were created with Biorender.com.

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