Restricted accessResearch articleFirst published online 2021-01
The Potent Antioxidant MitoQ Protects Against Preeclampsia During Late Gestation but Increases the Risk of Preeclampsia When Administered in Early Pregnancy
Although preeclampsia (PE) has been attributed to excessive oxidative stress (OS) in the placenta, mild antioxidants failed to prevent PE in clinical trials. As mitochondria are a major source of OS, this study assessed the potential of a potent mitochondria-targeting antioxidant MitoQ in the prevention of PE.
Results:
Placentas from women with PE and from reduced uterine perfusion pressure (RUPP) mice demonstrated significantly higher OS, along with increased mitochondrial damage and compromised glutathione peroxidase (GPx) activities. MitoQ administration during late gestation alleviated RUPP-induced PE; whereas early-pregnancy MitoQ treatment not only exacerbated blood pressure, fetal growth restriction, and proteinuria but also reduced the labyrinth/spongiotrophoblast ratio and blood sinuses in the labyrinth. Invasion (Matrigel transwell) and migration (wound healing assay) of trophoblasts were greatly improved by 1 μM hydrogen peroxide (H2O2), but this improvement was abolished by MitoQ or MitoTempo. Mild OS enhanced the expression of miR-29b-3p, which regulates five genes involved in viability and mobility, in HTR8-S/Vneo cells.
Innovation and Conclusions:
Although the potent mitochondrial-targeting antioxidant MitoQ protects against hypertension and kidney damage induced by RUPP in mice when administered in late gestation, it exacerbates the PE-like phenotype when given in early gestation by interfering with placenta formation because mild OS is required to stimulate trophoblast proliferation, invasion, and migration. Eliminating trophoblastic OS during early pregnancy may lead to compromised placentation and a risk of diseases of placental origin. Therefore, antioxidant therapy for pregnant women should be carefully considered.
Get full access to this article
View all access options for this article.
References
1.
American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 202 gestational hypertension and preeclampsia. Obstet Gynecol, 133: e1–e25, 2019.
2.
AlexanderBT, KassabSE, MillerMT, AbramSR, ReckelhoffJF, BennettWA, and GrangerJP. Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide. Hypertension, 37: 1191–1195, 2001.
3.
ArnandisT, MonteiroP, AdamsSD, BridgemanVL, RajeeveV, GadaletaE, MarzecJ, ChelalaC, MalanchiI, CutillasPR, and GodinhoSA. Oxidative stress in cells with extra centrosomes drives non-cell-autonomous invasion. Dev Cell, 47: 409.e9–424.e9, 2018.
4.
AutierP, BoniolM, PizotC, and MullieP. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol, 2: 76–89, 2014.
5.
BjelakovicG, NikolovaD, and GluudC. Antioxidant supplements and mortality. Curr Opin Clin Nutr Metab Care, 17: 40–44, 2014.
6.
BossAL, ChamleyLW, and JamesJL. Placental formation in early pregnancy: how is the centre of the placenta made?. Hum Reprod Update, 24: 750–760, 2018.
7.
BrosensI, PijnenborgR, VercruysseL, and RomeroR. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol, 204: 193–201, 2011.
8.
BurtonGJ and JauniauxE. Oxidative stress. Best Pract Res Clin Obstet Gynaecol, 25: 287–299, 2011.
9.
CavagisADM, FerreiraCV, VersteegHH, AssisCF, BosCL, BleumingSA, DiksSH, AoyamaH, and PeppelenboschMP. Tetrahydroxyquinone induces apoptosis of leukemia cells through diminished survival signaling. Exp Hematol, 34: 188–196, 2006.
10.
ChaiswingL, St ClairWH, and St ClairDK. Redox paradox: a novel approach to therapeutics-resistant cancer. Antioxid Redox Signal, 29: 1237–1272, 2018.
11.
Cindrova-DaviesT, FogartyNME, JonesCJP, KingdomJ, and BurtonGJ. Evidence of oxidative stress-induced senescence in mature, post-mature and pathological human placentas. Placenta, 68: 15–22, 2018.
12.
CrossCE, TolbaMF, RondelliCM, XuM, and Abdel-RahmanSZ. Oxidative stress alters miRNA and gene expression profiles in villous first trimester trophoblasts. Biomed Res Int, 2015: 257090, 2015.
13.
DikalovaAE, BikineyevaAT, BudzynK, NazarewiczRR, McCannL, LewisW, HarrisonDG, and DikalovSI. Therapeutic targeting of mitochondrial superoxide in hypertension. Circ Res, 107: 106–116, 2010.
14.
DowlingDK.Evolutionary perspectives on the links between mitochondrial genotype and disease phenotype. Biochim Biophys Acta, 1840: 1393–1403, 2014.
15.
FisherSJ.Why is placentation abnormal in preeclampsia?. Am J Obstet Gynecol, 213: S115–S122, 2015.
16.
FushimaT, SekimotoA, MinatoT, ItoT, OeY, KisuK, SatoE, FunamotoK, HayaseT, KimuraY, ItoS, SatoH, and TakahashiN. Reduced uterine perfusion pressure (RUPP) model of preeclampsia in mice. PLoS One, 11: e0155426, 2016.
17.
GrahamD, HuynhNN, HamiltonCA, BeattieE, SmithRA, CochemeHM, MurphyMP, and DominiczakAF. Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension, 54: 322–328, 2009.
18.
GrodsteinF, O'BrienJ, KangJH, DushkesR, CookNR, OkerekeO, MansonJE, GlynnRJ, BuringJE, GazianoM, and SessoHD. Long-term multivitamin supplementation and cognitive function in men: a randomized trial. Ann Intern Med, 159: 806–814, 2013.
19.
HeL and HannonGJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet, 5: 522–531, 2004.
20.
HollandO, NitertMD, GalloLA, VejzovicM, FisherJJ, and PerkinsAV. Review: placental mitochondrial function and structure in gestational disorders. Placenta, 54: 2–9, 2017.
21.
HolmstromKM and FinkelT. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol, 15: 411–421, 2014.
22.
HuD and CrossJC. Development and function of trophoblast giant cells in the rodent placenta. Int J Dev Biol, 54: 341–354, 2010.
23.
IlekisJV, TsilouE, FisherS, AbrahamsVM, SoaresMJ, CrossJC, ZamudioS, IllsleyNP, MyattL, ColvisC, CostantineMM, HaasDM, SadovskyY, WeinerC, RyttingE, and BidwellG. Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Am J Obstet Gynecol, 215: S1–S46, 2016.
24.
JamesAM, CochemeHM, SmithRA, and MurphyMP. Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools. J Biol Chem, 280: 21295–21312, 2005.
25.
JamesAM, SharpleyMS, ManasAR, FrermanFE, HirstJ, SmithRA, and MurphyMP. Interaction of the mitochondria-targeted antioxidant MitoQ with phospholipid bilayers and ubiquinone oxidoreductases. J Biol Chem, 282: 14708–14718, 2007.
26.
KelsoGF, PorteousCM, CoulterCV, HughesG, PorteousWK, LedgerwoodEC, SmithRAJ, and MurphyMP. Selective targeting of a redox-active ubiquinone to mitochondria within cells. J Biol Chem, 276: 4588–4596, 2001.
27.
KerleyRN, McCarthyC, KellDB, and KennyLC. The potential therapeutic effects of ergothioneine in pre-eclampsia. Free Radic Biol Med, 117: 145–157, 2018.
28.
KulcheskiFR, ChristoffAP, and MargisR. Circular RNAs are miRNA sponges and can be used as a new class of biomarker. J Biotechnol, 20: 42–51, 2016.
29.
LaneN and MartinW. The energetics of genome complexity. Nature, 467: 929–934, 2010.
30.
LiJ, LaMarcaB, and ReckelhoffJF. A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model. Am J Physiol Heart Circ Physiol, 303: H1–H8, 2012.
31.
LiJ, ZhouJ, TianB, ChuY, ZhangN, HuX, WanX, and YeY. Activation of HO-1 protects placental cells function in oxidative stress via regulating ZO-1/occludin. Biochem Biophys Res Commun, 511: 903–909, 2019.
32.
LiP, GuoW, DuL, ZhaoJ, WangY, LiuL, HuY, and HouY. microRNA-29b contributes to pre-eclampsia through its effects on apoptosis, invasion and angiogenesis of trophoblast cells. Clin Sci (Lond), 124: 27–40, 2013.
33.
LiPL.Cardiovascular pathobiology of inflammasomes: inflammatory machinery and beyond. Antioxid Redox Signal, 22: 1079–1083, 2015.
34.
LiangHL, SedlicF, BosnjakZ, and NilakantanV. SOD1 and MitoTEMPO partially prevent mitochondrial permeability transition pore opening, necrosis, and mitochondrial apoptosis after ATP depletion recovery. Free Radic Biol Med, 49: 1550–1560, 2010.
35.
LinJH, YangYK, LiuH, LinQD, and ZhangWY; Cooperation Group on Special Project “Study on the prevention and treatment for hypertension disorders and hematopexis related complications in pregnancy.” Effect of antioxidants on amelioration of high-risk factors inducing hypertensive disorders in pregnancy. Chin Med J (Engl) 123: 2548–2554, 2010.
36.
LiuZ, LiS, CaiY, WangA, HeQ, ZhengC, ZhaoT, DingX, and ZhouX. Manganese superoxide dismutase induces migration and invasion of tongue squamous cell carcinoma via H2O2-dependent Snail signaling. Free Radic Biol Med, 53: 44–50, 2012.
37.
Mauro-LizcanoM, Esteban-MartinezL, SecoE, Serrano-PueblaA, Garcia-LedoL, Figueiredo-PereiraC, VieiraHL, and BoyaP. New method to assess mitophagy flux by flow cytometry. Autophagy, 11: 833–843, 2015.
38.
McCarthyCM and KennyLC. Mitochondrial [dys]function; culprit in preecalmpsia. Clin Sci (Lond), 130: 1179–1184, 2016.
39.
MortonJS, LevasseurJ, GangulyE, QuonA, KirschenmanR, DyckJRB, FraserGM, and DavidgeST. Characterisation of the selective reduced uteroplacental perfusion (sRUPP) model of preeclampsia. Sci Rep, 9: 9565, 2019.
PhillipsTJ, ScottH, MenassaDA, BignellAL, SoodA, MortonJS, AkagiT, AzumaK, RogersMF, GilmoreCE, InmanGJ, GrantS, ChungY, AljunaidyMM, CookeCL, SteinkrausBR, PocklingtonA, LoganA, CollettGP, KempH, HolmansPA, MurphyMP, FulgaTA, ConeyAM, AkashiM, DavidgeST, and CaseCP. Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development. Sci Rep, 7: 9079, 2017.
44.
PostonL, BrileyAL, SeedPT, KellyFJ, and ShennanAH. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet, 367: 1145–1154, 2006.
RedmanCW and SargentIL. Latest advances in understanding preeclampsia. Science, 308: 1592–1594, 2005.
48.
RenshallLJ, MorganHL, MoensH, CansfieldD, Finn-SellSL, TropeaT, CottrellEC, GreenwoodS, SibleyCP, WareingM, and DilworthMR. Melatonin increases fetal weight in wild-type mice but not in mouse models of fetal growth restriction. Front Physiol, 9: 1141, 2018.
49.
RobertsJM and HubelCA. The two stage model of preeclampsia: variations on the theme. Placenta 30(Suppl, A): S32–S37, 2009.
50.
RobertsJM, MyattL, SpongCY, ThomEA, HauthJC, LevenoKJ, PearsonGD, WapnerRJ, VarnerMW, ThorpJMJr., MercerBM, PeacemanAM, RaminSM, CarpenterMW, SamuelsP, SciscioneA, HarperM, SmithWJ, SaadeG, SorokinY, and AndersonGB, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine UnitsNetwork.Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med, 362: 1282–1291, 2010.
51.
RumboldA, DuleyL, CrowtherC, and HaslamR. Antioxidants for preventing pre-eclampsia. Cochrane Database Syst Rev, 2008: CD004227, 2008.
52.
SarsourEH, KalenAL, and GoswamiPC. Manganese superoxide dismutase regulates a redox cycle within the cell cycle. Antioxid Redox Signal, 20: 1618–1627, 2014.
53.
Scherz-ShouvalR, ShvetsE, FassE, ShorerH, GilL, and ElazarZ. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J, 38: 1749–1760, 2019.
54.
SchieberM and ChandelNS. ROS function in redox signaling and oxidative stress. Curr Biol, 24: R453–R462, 2014.
55.
SimmonsDG, NataleDR, BegayV, HughesM, LeutzA, and CrossJC. Early patterning of the chorion leads to the trilaminar trophoblast cell structure in the placental labyrinth. Development, 135: 2083–2091, 2008.
56.
SimsNR and AndersonMF. Isolation of mitochondria from rat brain using Percoll density gradient centrifugation. Nat Protoc, 3: 1228–1239, 2008.
57.
SukjamnongS, ChanYL, ZakaryaR, SaadS, SharmaP, SantiyanontR, ChenH, and OliverBG. Effect of long-term maternal smoking on the offspring's lung health. Am J Physiol Lung Cell Mol Physiol, 313: L416–L423, 2017.
58.
TenorioMB, FerreiraRC, MouraFA, BuenoNB, GoulartMOF, and OliveiraACM. Oral antioxidant therapy for prevention and treatment of preeclampsia: meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis, 28: 865–876, 2018.
59.
ThomsonDW and DingerME. Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet, 17: 272–283, 2016.
60.
VakaVR, McMasterKM, CunninghamMWJr., IbrahimT, HazlewoodR, UsryN, CorneliusDC, AmaralLM, and LaMarcaB.Role of mitochondrial dysfunction and reactive oxygen species in mediating hypertension in the reduced uterine perfusion pressure rat model of preeclampsia. Hypertension, 72: 703–711, 2018.
61.
WatsonED and CrossJC. Development of structures and transport functions in the mouse placenta. Physiology (Bethesda), 20: 180–193, 2005.
62.
WieckowskiMR, GiorgiC, LebiedzinskaM, DuszynskiJ, and PintonP. Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells. Nat Protoc, 4: 1582–1590, 2009.
63.
WilliamsonRD, McCarthyC, McCarthyFP, and KennyLC. Oxidative stress in pre-eclampsia; have we been looking in the wrong place?. Pregnancy Hypertens, 8: 1–5, 2017.
64.
YangX, XuP, ZhangF, ZhangL, ZhengY, HuM, WangL, HanTL, PengC, WangL, WenL, ZengY, GaoR, XiaY, TongC, YangZ, QiH, and BakerPN. AMPK hyper-activation alters fatty acids metabolism and impairs invasiveness of trophoblasts in preeclampsia. Cell Physiol Biochem, 49: 578–594, 2018.
65.
YangY, AbdulhasanM, AwonugaA, BolnickA, PuscheckEE, and RappoleeDA. Hypoxic stress forces adaptive and maladaptive placental stress responses in early pregnancy. Birth Defects Res, 109: 1330–1344, 2017.
66.
YunJ and FinkelT. Mitohormesis. Cell Metab, 19: 757–766, 2014.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
