Abstract
During placentation, villous cytotrophoblast (CTB) stem cells proliferate and fuse, giving rise to the multinucleated syncytiotrophoblast (STB), which represents the terminally differentiated villous layer as well as the maternal-fetal interface. The syncytiotrophoblast is at the forefront of nutrient, gas, and waste exchange while also harboring essential endocrine functions to support pregnancy and fetal development. Considering that mitochondrial dynamics and respiration have been implicated in stem cell fate decisions of several cell types and that the placenta is a mitochondria-rich organ, we will highlight the role of mitochondria in facilitating trophoblast differentiation and maintaining trophoblast function. We discuss both the process of syncytialization and the distinct metabolic characteristics associated with CTB and STB sub-lineages prior to and during syncytialization. As mitochondrial respiration is tightly coupled to redox homeostasis, we emphasize the adaptations of mitochondrial respiration to the hypoxic placental environment. Furthermore, we highlight the critical role of mitochondria in conferring the steroidogenic potential of the STB following differentiation. Ultimately, mitochondrial function and morphological changes centrally regulate respiration and influence trophoblast fate decisions through the production of reactive oxygen species (ROS), whose levels modulate the transcriptional activation or suppression of pluripotency or commitment genes.
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References
Abbade J, Klemetti MM, Farrell A, Ermini L, Gillmore T, Sallais J, Caniggia I (2020) Increased placental mitochondrial fusion in gestational diabetes mellitus: an adaptive mechanism to optimize feto-placental metabolic homeostasis? BMJ Open Diabetes Res Care 8(1). https://doi.org/10.1136/bmjdrc-2019-000923
Afzal N, Lederer WJ, Jafri MS, Mannella CA (2021) Effect of crista morphology on mitochondrial ATP output: a computational study. Curr Res Physiol 4:163–176. https://doi.org/10.1016/j.crphys.2021.03.005
Agarwal I, Karumanchi SA (2011) Preeclampsia and the Anti-Angiogenic State. Pregnancy Hypertens 1(1):17–21. https://doi.org/10.1016/j.preghy.2010.10.007
Agostini M, Romeo F, Inoue S, Niklison-Chirou MV, Elia AJ, Dinsdale D et al (2016) Metabolic reprogramming during neuronal differentiation. Cell Death Differ 23(9):1502–1514. https://doi.org/10.1038/cdd.2016.36
Alison MR, Poulsom R, Forbes S, Wright NA (2002) An introduction to stem cells. J Pathol 197(4):419–423. https://doi.org/10.1002/path.1187
Allen JA, Shankara T, Janus P, Buck S, Diemer T, Hales KH, Hales DB (2006) Energized, polarized, and actively respiring mitochondria are required for acute Leydig cell steroidogenesis. Endocrinology 147(8):3924–3935. https://doi.org/10.1210/en.2005-1204
Alsat E, Wyplosz P, Malassiné A, Guibourdenche J, Porquet D, Nessmann C, Evain-Brion D (1996) Hypoxia impairs cell fusion and differentiation process in human cytotrophoblast, in vitro. J Cell Physiol 168(2):346–353. https://doi.org/10.1002/(SICI)1097-4652(199608)168:2<346::AID-JCP13>3.0.CO;2-1
Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J et al (1981) Sequence and organization of the human mitochondrial genome. Nature 290(5806):457–465. https://doi.org/10.1038/290457a0
Azuma K, Ikeda K, Inoue S (2020) Functional mechanisms of mitochondrial respiratory chain supercomplex assembly factors and their involvement in muscle quality. Int J Mol Sci 21(9). https://doi.org/10.3390/ijms21093182
Bainbridge SA, Minhas A, Whiteley KJ, Qu D, Sled JG, Kingdom JC, Adamson SL (2012) Effects of reduced Gcm1 expression on trophoblast morphology, fetoplacental vascularity, and pregnancy outcomes in mice. Hypertension 59(3):732–739. https://doi.org/10.1161/HYPERTENSIONAHA.111.183939
Baker N, Wade S, Triolo M, Girgis J, Chwastek D, Larrigan S et al (2022) The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells. Cell Stem Cell 29(9):1315–1332.e1319. https://doi.org/10.1016/j.stem.2022.07.010
Bartho LA, Fisher JJ, Cuffe JSM, Perkins AV (2020) Mitochondrial transformations in the aging human placenta. Am J Physiol Endocrinol Metab 319(6):E981–E994. https://doi.org/10.1152/ajpendo.00354.2020
Bax BE, Bloxam DL (1997) Energy metabolism and glycolysis in human placental trophoblast cells during differentiation. Biochim Biophys Acta 1319(2–3):283–292. https://doi.org/10.1016/s0005-2728(96)00169-7
Bigarella CL, Liang R, Ghaffari S (2014) Stem cells and the impact of ROS signaling. Development 141(22):4206–4218. https://doi.org/10.1242/dev.107086
Black S, Kadyrov M, Kaufmann P, Ugele B, Emans N, Huppertz B (2004) Syncytial fusion of human trophoblast depends on caspase 8. Cell Death Differ 11(1):90–98. https://doi.org/10.1038/sj.cdd.4401307
Blum TB, Hahn A, Meier T, Davies KM, Kühlbrandt W (2019) Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows. Proc Natl Acad Sci U S A 116(10):4250–4255. https://doi.org/10.1073/pnas.1816556116
Breckenridge DG, Stojanovic M, Marcellus RC, Shore GC (2003) Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J Cell Biol 160(7):1115–1127. https://doi.org/10.1083/jcb.200212059
Burman JL, Pickles S, Wang C, Sekine S, Vargas JNS, Zhang Z et al (2017) Mitochondrial fission facilitates the selective mitophagy of protein aggregates. J Cell Biol 216(10):3231–3247. https://doi.org/10.1083/jcb.201612106
Burton GJ, Jones CJ (2009) Syncytial knots, sprouts, apoptosis, and trophoblast deportation from the human placenta. Taiwan J Obstet Gynecol 48(1):28–37. https://doi.org/10.1016/S1028-4559(09)60032-2
Bustamante J, RamÃrez-Vélez R, Czerniczyniec A, Cicerchia D, Aguilar de Plata AC, Lores-Arnaiz S (2014) Oxygen metabolism in human placenta mitochondria. J Bioenerg Biomembr 46(6):459–469. https://doi.org/10.1007/s10863-014-9572-x
Calvo E, Cogliati S, Hernansanz-AgustÃn P, Loureiro-López M, Guarás A, Casuso RA et al (2020) Functional role of respiratory supercomplexes in mice: SCAF1 relevance and segmentation of the Qpool. Sci Adv 6(26):eaba7509. https://doi.org/10.1126/sciadv.aba7509
Chang CW, Wakeland AK, Parast MM (2018) Trophoblast lineage specification, differentiation and their regulation by oxygen tension. J Endocrinol 236(1):R43–R56. https://doi.org/10.1530/JOE-17-0402
Chen B, Longtine MS, Sadovsky Y, Nelson DM (2010) Hypoxia downregulates p53 but induces apoptosis and enhances expression of BAD in cultures of human syncytiotrophoblasts. Am J Physiol Cell Physiol 299(5):C968–C976. https://doi.org/10.1152/ajpcell.00154.2010
Chernomordik LV, Kozlov MM (2005) Membrane hemifusion: crossing a chasm in two leaps. Cell 123(3):375–382. https://doi.org/10.1016/j.cell.2005.10.015
Choi HJ, Sanders TA, Tormos KV, Ameri K, Tsai JD, Park AM et al (2013) ECM-dependent HIF induction directs trophoblast stem cell fate via LIMK1-mediated cytoskeletal rearrangement. PLoS One 8(2):e56949. https://doi.org/10.1371/journal.pone.0056949
Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L (2004) OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A 101(45):15927–15932. https://doi.org/10.1073/pnas.0407043101
Cogliati S, Calvo E, Loureiro M, Guaras AM, Nieto-Arellano R, Garcia-Poyatos C et al (2016) Mechanism of super-assembly of respiratory complexes III and IV. Nature 539(7630):579–582. https://doi.org/10.1038/nature20157
Coutifaris C, Kao LC, Sehdev HM, Chin U, Babalola GO, Blaschuk OW, Strauss JF (1991) E-cadherin expression during the differentiation of human trophoblasts. Development 113(3):767–777. https://doi.org/10.1242/dev.113.3.767
Cribbs JT, Strack S (2007) Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep 8(10):939–944. https://doi.org/10.1038/sj.embor.7401062
Cronier L, Defamie N, Dupays L, Théveniau-Ruissy M, Goffin F, Pointis G, Malassiné A (2002) Connexin expression and gap junctional intercellular communication in human first trimester trophoblast. Mol Hum Reprod 8(11):1005–1013. https://doi.org/10.1093/molehr/8.11.1005
Csapo AI, Pohanka O, Kaihola HL (1974) Progesterone deficiency and premature labour. Br Med J 1(5899):137–140. https://doi.org/10.1136/bmj.1.5899.137
Da Cruz S, Parone PA, Gonzalo P, Bienvenut WV, Tondera D, Jourdain A et al (2008) SLP-2 interacts with prohibitins in the mitochondrial inner membrane and contributes to their stability. Biochim Biophys Acta 1783(5):904–911. https://doi.org/10.1016/j.bbamcr.2008.02.006
Daskalakis G, Marinopoulos S, Krielesi V, Papapanagiotou A, Papantoniou N, Mesogitis S, Antsaklis A (2008) Placental pathology in women with gestational diabetes. Acta Obstet Gynecol Scand 87(4):403–407. https://doi.org/10.1080/00016340801908783
Daya S (1994) Issues in the etiology of recurrent spontaneous abortion. Curr Opin Obstet Gynecol 6(2):153–159
De los Rios Castillo D, Zarco-Zavala M, Olvera-Sanchez S, Pardo JP, Juarez O, Martinez F et al (2011) Atypical cristae morphology of human syncytiotrophoblast mitochondria: role for complex V. J Biol Chem 286(27):23911–23919. https://doi.org/10.1074/jbc.M111.252056
den Brave F, Becker T (2020) Supercomplex formation boosts respiration. EMBO Rep 21(12):e51830. https://doi.org/10.15252/embr.202051830
Duarte A, Poderoso C, Cooke M, Soria G, Cornejo Maciel F, Gottifredi V, Podestá EJ (2012) Mitochondrial fusion is essential for steroid biosynthesis. PLoS One 7(9):e45829. https://doi.org/10.1371/journal.pone.0045829
Duarte A, Castillo AF, Podestá EJ, Poderoso C (2014) Mitochondrial fusion and ERK activity regulate steroidogenic acute regulatory protein localization in mitochondria. PLoS One 9(6):e100387. https://doi.org/10.1371/journal.pone.0100387
Dupressoir A, Vernochet C, Bawa O, Harper F, Pierron G, Opolon P, Heidmann T (2009) Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene. Proc Natl Acad Sci U S A 106(29):12127–12132. https://doi.org/10.1073/pnas.0902925106
Elmore SP, Qian T, Grissom SF, Lemasters JJ (2001) The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J 15(12):2286–2287. https://doi.org/10.1096/fj.01-0206fje
Esnault C, Priet S, Ribet D, Vernochet C, Bruls T, Lavialle C et al (2008) A placenta-specific receptor for the fusogenic, endogenous retrovirus-derived, human syncytin-2. Proc Natl Acad Sci U S A 105(45):17532–17537. https://doi.org/10.1073/pnas.0807413105
Esparza-Moltó PB, Nuevo-Tapioles C, Cuezva JM (2017) Regulation of the H + -ATP synthase by IF1: a role in mitohormesis. Cell Mol Life Sci 74(12):2151–2166. https://doi.org/10.1007/s00018-017-2462-8
Fariss MW, Chan CB, Patel M, Van Houten B, Orrenius S (2005) Role of mitochondria in toxic oxidative stress. Mol Interv 5(2):94–111. https://doi.org/10.1124/mi.5.2.7
Fisher J, McKeating D, Pennell E, Cuffe J, Holland O, Perkins A (2019a) Mitochondrial isolation, cryopreservation and preliminary biochemical characterisation from placental cytotrophoblast and syncytiotrophoblast. Placenta 82:1–4. https://doi.org/10.1016/j.placenta.2019.05.004
Fisher JJ, McKeating DR, Cuffe JS, Bianco-Miotto T, Holland OJ, Perkins AV (2019b) Proteomic analysis of placental mitochondria following trophoblast differentiation. Front Physiol 10:1536. https://doi.org/10.3389/fphys.2019.01536
Flores-Herrera O, Olvera-Sánchez S, Esparza-PerusquÃa M, Pardo JP, Rendón JL, Mendoza-Hernández G, MartÃnez F (2015) Membrane potential regulates mitochondrial ATP-diphosphohydrolase activity but is not involved in progesterone biosynthesis in human syncytiotrophoblast cells. Biochim Biophys Acta 1847(2):143–152. https://doi.org/10.1016/j.bbabio.2014.10.002
Folmes CD, Nelson TJ, Martinez-Fernandez A, Arrell DK, Lindor JZ, Dzeja PP et al (2011) Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab 14(2):264–271. https://doi.org/10.1016/j.cmet.2011.06.011
Forni MF, Peloggia J, Trudeau K, Shirihai O, Kowaltowski AJ (2016) Murine mesenchymal stem cell commitment to differentiation is regulated by mitochondrial dynamics. Stem Cells 34(3):743–755. https://doi.org/10.1002/stem.2248
Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F et al (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1(4):515–525. https://doi.org/10.1016/s1534-5807(01)00055-7
Frendo JL, Olivier D, Cheynet V, Blond JL, Bouton O, Vidaud M et al (2003) Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation. Mol Cell Biol 23(10):3566–3574. https://doi.org/10.1128/MCB.23.10.3566-3574.2003
Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko GV, Rudka T et al (2006) OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126(1):177–189. https://doi.org/10.1016/j.cell.2006.06.025
GarcÃa-Poyatos C, Cogliati S, Calvo E, Hernansanz-AgustÃn P, Lagarrigue S, Magni R et al (2020) Scaf1 promotes respiratory supercomplexes and metabolic efficiency in zebrafish. EMBO Rep 21(7):e50287. https://doi.org/10.15252/embr.202050287
Gerbaud P, Pidoux G (2015) Review: an overview of molecular events occurring in human trophoblast fusion. Placenta 36(Suppl 1):S35–S42. https://doi.org/10.1016/j.placenta.2014.12.015
Germain M, Mathai JP, McBride HM, Shore GC (2005) Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis. EMBO J 24(8):1546–1556. https://doi.org/10.1038/sj.emboj.7600592
Getsios S, MacCalman CD (2003) Cadherin-11 modulates the terminal differentiation and fusion of human trophoblastic cells in vitro. Dev Biol 257(1):41–54. https://doi.org/10.1016/s0012-1606(03)00041-1
Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13(5):589–598. https://doi.org/10.1038/ncb2220
Gu W, Gaeta X, Sahakyan A, Chan AB, Hong CS, Kim R et al (2016) Glycolytic metabolism plays a functional role in regulating human pluripotent stem cell state. Cell Stem Cell 19(4):476–490. https://doi.org/10.1016/j.stem.2016.08.008
Hong HS, Mbah NE, Shan M, Loesel K, Lin L, Sajjakulnukit P et al (2022a) OXPHOS promotes apoptotic resistance and cellular persistence in T. Sci Immunol 7(77):eabm8182. https://doi.org/10.1126/sciimmunol.abm8182
Hong X, Isern J, Campanario S, Perdiguero E, RamÃrez-Pardo I, Segalés J et al (2022b) Mitochondrial dynamics maintain muscle stem cell regenerative competence throughout adult life by regulating metabolism and mitophagy. Cell Stem Cell 29(9):1298–1314.e1210. https://doi.org/10.1016/j.stem.2022.07.009
Hu C, Fan L, Cen P, Chen E, Jiang Z, Li L (2016a) Energy metabolism plays a critical role in stem cell maintenance and differentiation. Int J Mol Sci 17(2):253. https://doi.org/10.3390/ijms17020253
Hu Y, Li XC, Wang ZH, Luo Y, Zhang X, Liu XP et al (2016b) Tau accumulation impairs mitophagy via increasing mitochondrial membrane potential and reducing mitochondrial Parkin. Oncotarget 7(14):17356–17368. https://doi.org/10.18632/oncotarget.7861
Humphrey RG, Sonnenberg-Hirche C, Smith SD, Hu C, Barton A, Sadovsky Y, Nelson DM (2008) Epidermal growth factor abrogates hypoxia-induced apoptosis in cultured human trophoblasts through phosphorylation of BAD Serine 112. Endocrinology 149(5):2131–2137. https://doi.org/10.1210/en.2007-1253
Huppertz B, Gauster M (2011) Trophoblast fusion. Adv Exp Med Biol 713:81–95. https://doi.org/10.1007/978-94-007-0763-4_6
Huppertz B, Frank HG, Kingdom JC, Reister F, Kaufmann P (1998) Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta. Histochem Cell Biol 110(5):495–508. https://doi.org/10.1007/s004180050311
Huppertz B, Tews DS, Kaufmann P (2001) Apoptosis and syncytial fusion in human placental trophoblast and skeletal muscle. Int Rev Cytol 205:215–253. https://doi.org/10.1016/s0074-7696(01)05005-7
Hussain MU, Kremer M, Zoidl G, Dermietzel R (2003) Transcriptional and translational regulation of zebrafish connexin 55.5 (zf.Cx.55.5) and connexin 52.6 (zf.Cx52.6). Cell Commun Adhes 10(4–6):227–231
Ikeda K, Shiba S, Horie-Inoue K, Shimokata K, Inoue S (2013) A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle. Nat Commun 4:2147. https://doi.org/10.1038/ncomms3147
Ji L, Brkić J, Liu M, Fu G, Peng C, Wang YL (2013) Placental trophoblast cell differentiation: physiological regulation and pathological relevance to preeclampsia. Mol Aspects Med 34(5):981–1023. https://doi.org/10.1016/j.mam.2012.12.008
Jonckheere AI, Smeitink JA, Rodenburg RJ (2012) Mitochondrial ATP synthase: architecture, function and pathology. J Inherit Metab Dis 35(2):211–225. https://doi.org/10.1007/s10545-011-9382-9
Karbowski M, Lee YJ, Gaume B, Jeong SY, Frank S, Nechushtan A et al (2002) Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol 159(6):931–938. https://doi.org/10.1083/jcb.200209124
Kashatus JA, Nascimento A, Myers LJ, Sher A, Byrne FL, Hoehn KL et al (2015) Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell 57(3):537–551. https://doi.org/10.1016/j.molcel.2015.01.002
Kelly SJ (1977) Studies of the developmental potential of 4- and 8-cell stage mouse blastomeres. J Exp Zool 200(3):365–376. https://doi.org/10.1002/jez.1402000307
Khacho M, Slack RS (2017) Mitochondrial and reactive oxygen species signaling coordinate stem cell fate decisions and life long maintenance. Antioxid Redox Signal. https://doi.org/10.1089/ars.2017.7228
Khacho M, Clark A, Svoboda DS, Azzi J, MacLaurin JG, Meghaizel C et al (2016) Mitochondrial dynamics impacts stem cell identity and fate decisions by regulating a nuclear transcriptional program. Cell Stem Cell 19(2):232–247. https://doi.org/10.1016/j.stem.2016.04.015
Knerr I, Schubert SW, Wich C, Amann K, Aigner T, Vogler T et al (2005) Stimulation of GCMa and syncytin via cAMP mediated PKA signaling in human trophoblastic cells under normoxic and hypoxic conditions. FEBS Lett 579(18):3991–3998. https://doi.org/10.1016/j.febslet.2005.06.029
Kolahi KS, Valent AM, Thornburg KL (2017) Cytotrophoblast, not syncytiotrophoblast, dominates glycolysis and oxidative phosphorylation in human term placenta. Sci Rep 7:42941. https://doi.org/10.1038/srep42941
Kornfeld OS, Qvit N, Haileselassie B, Shamloo M, Bernardi P, Mochly-Rosen D (2018) Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo. Sci Rep 8(1):14034. https://doi.org/10.1038/s41598-018-32228-1
Kumar P, Mendelson CR (2011) Estrogen-related receptor gamma (ERRgamma) mediates oxygen-dependent induction of aromatase (CYP19) gene expression during human trophoblast differentiation. Mol Endocrinol 25(9):1513–1526. https://doi.org/10.1210/me.2011-1012
Lacher SE, Levings DC, Freeman S, Slattery M (2018) Identification of a functional antioxidant response element at the HIF1A locus. Redox Biol 19:401–411. https://doi.org/10.1016/j.redox.2018.08.014
Lager S, Powell TL (2012) Regulation of nutrient transport across the placenta. J Pregnancy 2012:179827. https://doi.org/10.1155/2012/179827
Lappas M, Hiden U, Desoye G, Froehlich J, Hauguel-de Mouzon S, Jawerbaum A (2011) The role of oxidative stress in the pathophysiology of gestational diabetes mellitus. Antioxid Redox Signal 15(12):3061–3100. https://doi.org/10.1089/ars.2010.3765
Lavillette D, Marin M, Ruggieri A, Mallet F, Cosset FL, Kabat D (2002) The envelope glycoprotein of human endogenous retrovirus type W uses a divergent family of amino acid transporters/cell surface receptors. J Virol 76(13):6442–6452. https://doi.org/10.1128/jvi.76.13.6442-6452.2002
Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15(11):5001–5011. https://doi.org/10.1091/mbc.e04-04-0294
Letts JA, Sazanov LA (2017) Clarifying the supercomplex: the higher-order organization of the mitochondrial electron transport chain. Nat Struct Mol Biol 24(10):800–808. https://doi.org/10.1038/nsmb.3460
Li L, Xie T (2005) Stem cell niche: structure and function. Annu Rev Cell Dev Biol 21:605–631. https://doi.org/10.1146/annurev.cellbio.21.012704.131525
Li H, Dakour J, Kaufman S, Guilbert LJ, Winkler-Lowen B, Morrish DW (2003) Adrenomedullin is decreased in preeclampsia because of failed response to epidermal growth factor and impaired syncytialization. Hypertension 42(5):895–900. https://doi.org/10.1161/01.HYP.0000095613.41961.6E
Liu X, Zuo R, Bao Y, Qu X, Sun K, Ying H (2017) Down-regulation of PDK4 is critical for the switch of carbohydrate catabolism during syncytialization of human placental trophoblasts. Sci Rep 7(1):8474. https://doi.org/10.1038/s41598-017-09163-8
Losón OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24(5):659–667. https://doi.org/10.1091/mbc.E12-10-0721
Lunt SY, Vander Heiden MG (2011) Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 27:441–464. https://doi.org/10.1146/annurev-cellbio-092910-154237
Madazli R, Benian A, Aydin S, Uzun H, Tolun N (2002) The plasma and placental levels of malondialdehyde, glutathione and superoxide dismutase in pre-eclampsia. J Obstet Gynaecol 22(5):477–480. https://doi.org/10.1080/0144361021000003573
Malassiné A, Frendo JL, Blaise S, Handschuh K, Gerbaud P, Tsatsaris V et al (2008) Human endogenous retrovirus-FRD envelope protein (syncytin 2) expression in normal and trisomy 21-affected placenta. Retrovirology 5:6. https://doi.org/10.1186/1742-4690-5-6
Maltepe E, Krampitz GW, Okazaki KM, Red-Horse K, Mak W, Simon MC, Fisher SJ (2005) Hypoxia-inducible factor-dependent histone deacetylase activity determines stem cell fate in the placenta. Development 132(15):3393–3403. https://doi.org/10.1242/dev.01923
MartÃnez F, Kiriakidou M, Strauss JF (1997) Structural and functional changes in mitochondria associated with trophoblast differentiation: methods to isolate enriched preparations of syncytiotrophoblast mitochondria. Endocrinology 138(5):2172–2183. https://doi.org/10.1210/endo.138.5.5133
Martinez F, Olvera-Sanchez S, Esparza-Perusquia M, Gomez-Chang E, Flores-Herrera O (2015) Multiple functions of syncytiotrophoblast mitochondria. Steroids 103:11–22. https://doi.org/10.1016/j.steroids.2015.09.006
Matsubara K, Higaki T, Matsubara Y, Nawa A (2015) Nitric oxide and reactive oxygen species in the pathogenesis of preeclampsia. Int J Mol Sci 16(3):4600–4614. https://doi.org/10.3390/ijms16034600
Mayhew TM, Leach L, McGee R, Ismail WW, Myklebust R, Lammiman MJ (1999) Proliferation, differentiation and apoptosis in villous trophoblast at 13-41 weeks of gestation (including observations on annulate lamellae and nuclear pore complexes). Placenta 20(5–6):407–422. https://doi.org/10.1053/plac.1999.0399
Merkwirth C, Dargazanli S, Tatsuta T, Geimer S, Löwer B, Wunderlich FT et al (2008) Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria. Genes Dev 22(4):476–488. https://doi.org/10.1101/gad.460708
Mi S, Lee X, Li X, Veldman GM, Finnerty H, Racie L et al (2000) Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403(6771):785–789. https://doi.org/10.1038/35001608
Mishra P, Chan DC (2016) Metabolic regulation of mitochondrial dynamics. J Cell Biol 212(4):379–387. https://doi.org/10.1083/jcb.201511036
Mitsopoulos P, Chang YH, Wai T, König T, Dunn SD, Langer T, Madrenas J (2015) Stomatin-like protein 2 is required for in vivo mitochondrial respiratory chain supercomplex formation and optimal cell function. Mol Cell Biol 35(10):1838–1847. https://doi.org/10.1128/MCB.00047-15
Myatt L (2010) Review: reactive oxygen and nitrogen species and functional adaptation of the placenta. Placenta 31 Suppl(Suppl):S66–S69. https://doi.org/10.1016/j.placenta.2009.12.021
Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183(5):795–803. https://doi.org/10.1083/jcb.200809125
Newhouse SM, Davidge ST, Winkler-Lowen B, Demianczuk N, Guilbert LJ (2007) In vitro differentiation of villous trophoblasts from pregnancies complicated by intrauterine growth restriction with and without pre-eclampsia. Placenta 28(10):999–1003. https://doi.org/10.1016/j.placenta.2007.04.008
Ochoa-Bernal MA, Fazleabas AT (2020) Physiologic events of embryo implantation and decidualization in human and non-human primates. Int J Mol Sci 21(6). https://doi.org/10.3390/ijms21061973
Oda H, Takeichi M (2011) Evolution: structural and functional diversity of cadherin at the adherens junction. J Cell Biol 193(7):1137–1146. https://doi.org/10.1083/jcb.201008173
Okahara G, Matsubara S, Oda T, Sugimoto J, Jinno Y, Kanaya F (2004) Expression analyses of human endogenous retroviruses (HERVs): tissue-specific and developmental stage-dependent expression of HERVs. Genomics 84(6):982–990. https://doi.org/10.1016/j.ygeno.2004.09.004
Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P, Lenaers G (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278(10):7743–7746. https://doi.org/10.1074/jbc.C200677200
Ono T, Isobe K, Nakada K, Hayashi JI (2001) Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat Genet 28(3):272–275. https://doi.org/10.1038/90116
Parameshwar PK, Sagrillo-Fagundes L, Fournier C, Girard S, Vaillancourt C, Moraes C (2021) Disease-specific extracellular matrix composition regulates placental trophoblast fusion efficiency. Biomater Sci 9(21):7247–7256. https://doi.org/10.1039/d1bm00799h
Parra V, Verdejo HE, Iglewski M, Del Campo A, Troncoso R, Jones D et al (2014) Insulin stimulates mitochondrial fusion and function in cardiomyocytes via the Akt-mTOR-NFκB-Opa-1 signaling pathway. Diabetes 63(1):75–88. https://doi.org/10.2337/db13-0340
Patten DA, Wong J, Khacho M, Soubannier V, Mailloux RJ, Pilon-Larose K et al (2014) OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand. EMBO J 33(22):2676–2691. https://doi.org/10.15252/embj.201488349
Pidoux G, Gerbaud P, Gnidehou S, Grynberg M, Geneau G, Guibourdenche J et al (2010) ZO-1 is involved in trophoblastic cell differentiation in human placenta. Am J Physiol Cell Physiol 298(6):C1517–C1526. https://doi.org/10.1152/ajpcell.00484.2008
Pidoux G, Gerbaud P, Dompierre J, Lygren B, Solstad T, Evain-Brion D, Taskén K (2014) A PKA-ezrin-Cx43 signaling complex controls gap junction communication and thereby trophoblast cell fusion. J Cell Sci 127(Pt 19):4172–4185. https://doi.org/10.1242/jcs.149609
Poidatz D, Dos Santos E, Brulé A, De Mazancourt P, Dieudonné MN (2012) Estrogen-related receptor gamma modulates energy metabolism target genes in human trophoblast. Placenta 33(9):688–695. https://doi.org/10.1016/j.placenta.2012.06.002
Poidatz D, Dos Santos E, Gronier H, Vialard F, Maury B, De Mazancourt P, Dieudonné MN (2015) Trophoblast syncytialisation necessitates mitochondrial function through estrogen-related receptor-γ activation. Mol Hum Reprod 21(2):206–216. https://doi.org/10.1093/molehr/gau102
Pötgens AJ, Drewlo S, Kokozidou M, Kaufmann P (2004) Syncytin: the major regulator of trophoblast fusion? Recent developments and hypotheses on its action. Hum Reprod Update 10(6):487–496. https://doi.org/10.1093/humupd/dmh039
Rajakumar A, Cerdeira AS, Rana S, Zsengeller Z, Edmunds L, Jeyabalan A et al (2012) Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia. Hypertension 59(2):256–264. https://doi.org/10.1161/HYPERTENSIONAHA.111.182170
Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J (2011) Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci U S A 108(25):10190–10195. https://doi.org/10.1073/pnas.1107402108
Renaud SJ, Jeyarajah MJ (2022) How trophoblasts fuse: an in-depth look into placental syncytiotrophoblast formation. Cell Mol Life Sci 79(8):433. https://doi.org/10.1007/s00018-022-04475-z
Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA, Mannella CA, Korsmeyer SJ (2002) A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2(1):55–67. https://doi.org/10.1016/s1534-5807(01)00116-2
Shi QJ, Lei ZM, Rao CV, Lin J (1993) Novel role of human chorionic gonadotropin in differentiation of human cytotrophoblasts. Endocrinology 132(3):1387–1395. https://doi.org/10.1210/endo.132.3.7679981
Shikita M, Hall PF (1973) Cytochrome P-450 from bovine adrenocortical mitochondria: an enzyme for the side chain cleavage of cholesterol. I. Purification and properties. J Biol Chem 248(16):5598–5604
Shyh-Chang N, Ng HH (2017) The metabolic programming of stem cells. Genes Dev 31(4):336–346. https://doi.org/10.1101/gad.293167.116
Simsek T, Kocabas F, Zheng J, Deberardinis RJ, Mahmoud AI, Olson EN et al (2010) The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7(3):380–390. https://doi.org/10.1016/j.stem.2010.07.011
Song Z, Ghochani M, McCaffery JM, Frey TG, Chan DC (2009) Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol Biol Cell 20(15):3525–3532. https://doi.org/10.1091/mbc.e09-03-0252
Takeda Y, Liu X, Sumiyoshi M, Matsushima A, Shimohigashi M, Shimohigashi Y (2009) Placenta expressing the greatest quantity of bisphenol A receptor ERR{gamma} among the human reproductive tissues: predominant expression of type-1 ERRgamma isoform. J Biochem 146(1):113–122. https://doi.org/10.1093/jb/mvp049
Takeichi M (1995) Morphogenetic roles of classic cadherins. Curr Opin Cell Biol 7(5):619–627. https://doi.org/10.1016/0955-0674(95)80102-2
Tang Y, Luo B, Deng Z, Wang B, Liu F, Li J et al (2016) Mitochondrial aerobic respiration is activated during hair follicle stem cell differentiation, and its dysfunction retards hair regeneration. PeerJ 4:e1821. https://doi.org/10.7717/peerj.1821
Tatapudy S, Aloisio F, Barber D, Nystul T (2017) Cell fate decisions: emerging roles for metabolic signals and cell morphology. EMBO Rep 18(12):2105–2118. https://doi.org/10.15252/embr.201744816
Tuckey RC (2005) Progesterone synthesis by the human placenta. Placenta 26(4):273–281. https://doi.org/10.1016/j.placenta.2004.06.012
Vangrieken P, Al-Nasiry S, Bast A, Leermakers PA, Tulen CBM, Schiffers PMH et al (2021) Placental mitochondrial abnormalities in preeclampsia. Reprod Sci 28(8):2186–2199. https://doi.org/10.1007/s43032-021-00464-y
Vargas A, Moreau J, Landry S, LeBellego F, Toufaily C, Rassart E et al (2009) Syncytin-2 plays an important role in the fusion of human trophoblast cells. J Mol Biol 392(2):301–318. https://doi.org/10.1016/j.jmb.2009.07.025
Wakeland AK, Soncin F, Moretto-Zita M, Chang CW, Horii M, Pizzo D et al (2017) Hypoxia directs human extravillous trophoblast differentiation in a hypoxia-inducible factor-dependent manner. Am J Pathol 187(4):767–780. https://doi.org/10.1016/j.ajpath.2016.11.018
Wasilewski M, Semenzato M, Rafelski SM, Robbins J, Bakardjiev AI, Scorrano L (2012) Optic atrophy 1-dependent mitochondrial remodeling controls steroidogenesis in trophoblasts. Curr Biol 22(13):1228–1234. https://doi.org/10.1016/j.cub.2012.04.054
Wich C, Kausler S, Dotsch J, Rascher W, Knerr I (2009) Syncytin-1 and glial cells missing a: hypoxia-induced deregulated gene expression along with disordered cell fusion in primary term human trophoblasts. Gynecol Obstet Invest 68(1):9–18. https://doi.org/10.1159/000209396
Willems PH, Rossignol R, Dieteren CE, Murphy MP, Koopman WJ (2015) Redox homeostasis and mitochondrial dynamics. Cell Metab 22(2):207–218. https://doi.org/10.1016/j.cmet.2015.06.006
Wong MK, Shawky SA, Aryasomayajula A, Green MA, Ewart T, Selvaganapathy PR, Raha S (2018) Extracellular matrix surface regulates self-assembly of three-dimensional placental trophoblast spheroids. PLoS One 13(6):e0199632. https://doi.org/10.1371/journal.pone.0199632
Wu W, Zhao D, Shah SZA, Zhang X, Lai M, Yang D et al (2019) OPA1 overexpression ameliorates mitochondrial cristae remodeling, mitochondrial dysfunction, and neuronal apoptosis in prion diseases. Cell Death Dis 10(10):710. https://doi.org/10.1038/s41419-019-1953-y
Wu C, Yao W, Kai W, Liu W, Wang W, Li S et al (2020) Mitochondrial fusion machinery specifically involved in energy deprivation-induced autophagy. Front Cell Dev Biol 8:221. https://doi.org/10.3389/fcell.2020.00221
Yang M, Lei ZM, Rao CV (2003) The central role of human chorionic gonadotropin in the formation of human placental syncytium. Endocrinology 144(3):1108–1120. https://doi.org/10.1210/en.2002-220922
Yang F, Zheng Q, Jin L (2019) Dynamic function and composition changes of immune cells during normal and pathological pregnancy at the maternal-fetal interface. Front Immunol 10:2317. https://doi.org/10.3389/fimmu.2019.02317
Yao CH, Wang R, Wang Y, Kung CP, Weber JD, Patti GJ (2019) Mitochondrial fusion supports increased oxidative phosphorylation during cell proliferation. Elife 8. https://doi.org/10.7554/eLife.41351
Yasuda M, Umemura S, Osamura RY, Kenjo T, Tsutsumi Y (1995) Apoptotic cells in the human endometrium and placental villi: pitfalls in applying the TUNEL method. Arch Histol Cytol 58(2):185–190. https://doi.org/10.1679/aohc.58.185
Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337(6098):1062–1065. https://doi.org/10.1126/science.1219855
Yung HW, Alnæs-Katjavivi P, Jones CJ, El-Bacha T, Golic M, Staff AC, Burton GJ (2016) Placental endoplasmic reticulum stress in gestational diabetes: the potential for therapeutic intervention with chemical chaperones and antioxidants. Diabetologia 59(10):2240–2250. https://doi.org/10.1007/s00125-016-4040-2
Zeldovich VB, Clausen CH, Bradford E, Fletcher DA, Maltepe E, Robbins JR, Bakardjiev AI (2013) Placental syncytium forms a biophysical barrier against pathogen invasion. PLoS Pathog 9(12):e1003821. https://doi.org/10.1371/journal.ppat.1003821
Zhang Y, Marsboom G, Toth PT, Rehman J (2013) Mitochondrial respiration regulates adipogenic differentiation of human mesenchymal stem cells. PLoS One 8(10):e77077. https://doi.org/10.1371/journal.pone.0077077
Zheng X, Boyer L, Jin M, Mertens J, Kim Y, Ma L et al (2016) Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation. Elife 5. https://doi.org/10.7554/eLife.13374
Zhong X, Cui P, Cai Y, Wang L, He X, Long P et al (2019) Mitochondrial dynamics is critical for the full pluripotency and embryonic developmental potential of pluripotent stem cells. Cell Metab 29(4):979–992.e974. https://doi.org/10.1016/j.cmet.2018.11.007
Zhu C, Yang H, Geng Q, Ma Q, Long Y, Zhou C, Chen M (2015) Association of oxidative stress biomarkers with gestational diabetes mellitus in pregnant women: a case-control study. PLoS One 10(4):e0126490. https://doi.org/10.1371/journal.pone.0126490
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Podinić, T., MacAndrew, A., Raha, S. (2024). Trophoblast Syncytialization: A Metabolic Crossroads. In: Kloc, M., Uosef, A. (eds) Syncytia: Origin, Structure, and Functions. Results and Problems in Cell Differentiation, vol 71. Springer, Cham. https://doi.org/10.1007/978-3-031-37936-9_6
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