Placental Mitochondrial Dysfunction with Metabolic Diseases: Therapeutic Approaches

Overview

Journal Biochim Biophys Acta Mol Basis Dis

Publisher Elsevier

Specialties Biochemistry
Biophysics
Genetics
Molecular Biology

Date 2020 Sep 13

PMID 32920120

Citations 24

Authors

Jessica F Hebert

Leslie Myatt

Affiliations

Soon will be listed here.

Abstract

Both obesity and gestational diabetes mellitus (GDM) lead to poor maternal and fetal outcomes, including pregnancy complications, fetal growth issues, stillbirth, and developmental programming of adult-onset disease in the offspring. Increased placental oxidative/nitrative stress and reduced placental (trophoblast) mitochondrial respiration occur in association with the altered maternal metabolic milieu of obesity and GDM. The effect is particularly evident when the fetus is male, suggesting a sexually dimorphic influence on the placenta. In addition, obesity and GDM are associated with inflexibility in trophoblast, limiting the ability to switch between usage of glucose, fatty acids, and glutamine as substrates for oxidative phosphorylation, again in a sexually dimorphic manner. Here we review mechanisms underlying placental mitochondrial dysfunction: its relationship to maternal and fetal outcomes and the influence of fetal sex. Prevention of placental oxidative stress and mitochondrial dysfunction may improve pregnancy outcomes. We outline pathways to ameliorate deficient mitochondrial respiration, particularly the benefits and pitfalls of mitochondria-targeted antioxidants.

Citing Articles

Perinatal obesity primes the hepatic metabolic stress response in the offspring across life span.

Stegmann S, Vohlen C, Im N, Niehues J, Selle J, Janoschek R Sci Rep. 2025; 15(1):6416.

PMID: 39984579 PMC: 11845730. DOI: 10.1038/s41598-025-90082-4.

Sexual dimorphism in lipidomic changes in maternal blood and placenta associated with obesity and gestational diabetes: A discovery study.

Kadam L, Velickovic M, Stratton K, Nicora C, Kyle J, Wang E Placenta. 2024; 159():76-83.

PMID: 39662110 PMC: 11729490. DOI: 10.1016/j.placenta.2024.12.002.

Chemerin alleviates the placental oxidative stress and improves fetal overgrowth of gestational diabetes mellitus mice induced by high fat diet.

Zhou X, Jiang Y, Wang Z, Wei L, Zhang H, Fang C Mol Med. 2024; 30(1):239.

PMID: 39616329 PMC: 11607826. DOI: 10.1186/s10020-024-01007-2.

Miro2 sulfhydration by CBS/HS promotes human trophoblast invasion and migration via regulating mitochondria dynamics.

Feng H, Sun Z, Han B, Xia H, Chen L, Tian C Cell Death Dis. 2024; 15(10):776.

PMID: 39461943 PMC: 11513031. DOI: 10.1038/s41419-024-07167-7.

NAD depletion is central to placental dysfunction in an inflammatory subclass of preeclampsia.

Jahan F, Vasam G, Cariaco Y, Nik-Akhtar A, Green A, Menzies K Life Sci Alliance. 2024; 7(12).

PMID: 39389781 PMC: 11467044. DOI: 10.26508/lsa.202302505.

References

Baker H, Frank O, DeAngelis B, Feingold S, KAMINETZKY H . Role of placenta in maternal-fetal vitamin transfer in humans. Am J Obstet Gynecol. 1981; 141(7):792-6. DOI: 10.1016/0002-9378(81)90706-7. View

Gong S, Johnson M, Dopierala J, Gaccioli F, Sovio U, Constancia M . Genome-wide oxidative bisulfite sequencing identifies sex-specific methylation differences in the human placenta. Epigenetics. 2018; 13(3):228-239. PMC: 5989156. DOI: 10.1080/15592294.2018.1429857. View

Smirnakis K, Martinez A, Blatman K, Wolf M, Ecker J, Thadhani R . Early pregnancy insulin resistance and subsequent gestational diabetes mellitus. Diabetes Care. 2005; 28(5):1207-8. DOI: 10.2337/diacare.28.5.1207. View

Maged A, Torky H, Fouad M, GadAllah S, Waked N, Gayed A . Role of antioxidants in gestational diabetes mellitus and relation to fetal outcome: a randomized controlled trial. J Matern Fetal Neonatal Med. 2016; 29(24):4049-54. DOI: 10.3109/14767058.2016.1154526. View

Hofstee P, Bartho L, McKeating D, Radenkovic F, McEnroe G, Fisher J . Maternal selenium deficiency during pregnancy in mice increases thyroid hormone concentrations, alters placental function and reduces fetal growth. J Physiol. 2019; 597(23):5597-5617. DOI: 10.1113/JP278473. View

Graham D, Huynh N, Hamilton C, Beattie E, Smith R, Cocheme H . Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension. 2009; 54(2):322-8. DOI: 10.1161/HYPERTENSIONAHA.109.130351. View

Baeten J, Bukusi E, Lambe M . Pregnancy complications and outcomes among overweight and obese nulliparous women. Am J Public Health. 2001; 91(3):436-40. PMC: 1446581. DOI: 10.2105/ajph.91.3.436. View

Guan Z, Li H, Guo L, Yang X . Effects of vitamin C, vitamin E, and molecular hydrogen on the placental function in trophoblast cells. Arch Gynecol Obstet. 2015; 292(2):337-42. DOI: 10.1007/s00404-015-3647-8. View

Ferey J, Boudoures A, Reid M, Drury A, Scheaffer S, Modi Z . A maternal high-fat, high-sucrose diet induces transgenerational cardiac mitochondrial dysfunction independently of maternal mitochondrial inheritance. Am J Physiol Heart Circ Physiol. 2019; 316(5):H1202-H1210. PMC: 6580388. DOI: 10.1152/ajpheart.00013.2019. View

10.

Holland O, Hickey A, Alvsaker A, Moran S, Hedges C, Chamley L . Changes in mitochondrial respiration in the human placenta over gestation. Placenta. 2017; 57:102-112. DOI: 10.1016/j.placenta.2017.06.011. View

11.

Myatt L . Review: Reactive oxygen and nitrogen species and functional adaptation of the placenta. Placenta. 2010; 31 Suppl:S66-9. PMC: 2832707. DOI: 10.1016/j.placenta.2009.12.021. View

12.

McGarry J, Brown N . The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem. 1997; 244(1):1-14. DOI: 10.1111/j.1432-1033.1997.00001.x. View

13.

Boyd P, BROWN R, Coghill G, SLIDDERS W, STEWART W . Measurement of the mass of syncytiotrophoblast in a range of human placentae using an image analysing computer. Placenta. 1983; 4(3):255-62. DOI: 10.1016/s0143-4004(83)80004-6. View

14.

Bray G . Complications of obesity. Ann Intern Med. 1985; 103(6 ( Pt 2)):1052-62. DOI: 10.7326/0003-4819-103-6-1052. View

15.

Guo C, Sun L, Chen X, Zhang D . Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2014; 8(21):2003-14. PMC: 4145906. DOI: 10.3969/j.issn.1673-5374.2013.21.009. View

16.

Mando C, Anelli G, Novielli C, Panina-Bordignon P, Massari M, Mazzocco M . Impact of Obesity and Hyperglycemia on Placental Mitochondria. Oxid Med Cell Longev. 2018; 2018:2378189. PMC: 6112210. DOI: 10.1155/2018/2378189. View

17.

Harman D . The biologic clock: the mitochondria?. J Am Geriatr Soc. 1972; 20(4):145-7. DOI: 10.1111/j.1532-5415.1972.tb00787.x. View

18.

Yao R, Ananth C, Park B, Pereira L, Plante L . Obesity and the risk of stillbirth: a population-based cohort study. Am J Obstet Gynecol. 2014; 210(5):457.e1-9. DOI: 10.1016/j.ajog.2014.01.044. View

19.

Muralimanoharan S, Maloyan A, Myatt L . Mitochondrial function and glucose metabolism in the placenta with gestational diabetes mellitus: role of miR-143. Clin Sci (Lond). 2016; 130(11):931-41. PMC: 4918818. DOI: 10.1042/CS20160076. View

20.

Lappas M, Hiden U, Desoye G, Froehlich J, Hauguel-De Mouzon S, Jawerbaum A . The role of oxidative stress in the pathophysiology of gestational diabetes mellitus. Antioxid Redox Signal. 2011; 15(12):3061-100. DOI: 10.1089/ars.2010.3765. View