Abstract
Aims
To better understand the role of oxidative stress in fetal programming, we assessed
the hypothesis that the mitochondrial translocation of human telomerase reverse transcriptase
(hTERT) could protect neonatal mitochondrial DNA (mtDNA) from oxidative damage during
pregnancies complicated by gestational diabetes mellitus (GDM).
Methods
26 GDM mothers and 47 controls and their newborns were enrolled. The plasma levels
of 8-isoprostaglandin F2α in maternal and cord blood were measured to evaluate oxidative stress. Western blotting
was then used to assess the mitochondrial localization of hTERT in cord blood mononuclear
cells (CBMCs). Finally, the relative mtDNA content was analyzed by real-time PCR.
Results
GDM mothers and their newborns had significantly higher levels of oxidative stress
than controls. hTERT was localized in both the nuclei and mitochondria of CBMCs, and
the increased CBMC mitochondrial hTERT levels were significantly correlated with elevated
oxidative stress in newborns. The neonatal mtDNA content in the GDM group was comparable
to controls, and was positively correlated with mitochondrial hTERT levels in CBMCs,
suggesting that mitochondrial hTERT in CBMCs may have a protective effect on neonatal
mtDNA in GDM pregnancies.
Conclusions
This study is the first to suggest that the mitochondrial translocation of hTERT in
CBMCs under heightened oxidative stress might protect neonatal mtDNA from oxidative
damage in GDM pregnancies. This could be an in utero adaptive response of a fetus that is suffering from elevated oxidative stress, and
could help our understanding of the roles of oxidative stress in fetal programming.
Keywords
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References
- Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. The Organizing Committee.Diabetes Care. 1998; 21: B161
- Genetics of gestational diabetes mellitus.Curr Med Chem. 2007; 14: 569-583
- Early manifestation of cardiovascular disease risk factors in offspring of mothers with previous history of gestational diabetes mellitus.Diabetes Res Clin Pract. 2007; 78: 238-245
- The fetal and maternal consequences of gestational diabetes mellitus.J Matern Fetal Neonatal Med. 2010; 23: 199-203
- Disproportionate body composition and neonatal outcome in offspring of mothers with and without gestational diabetes mellitus.Diabetes Care. 2013; 36: 3543-3548
- Impact of maternal diabetes on epigenetic modifications leading to diseases in the offspring.Exp Diabetes Res. 2012; 2012: 538474
- Higher fetal insulin resistance in Chinese pregnant women with gestational diabetes mellitus and correlation with maternal insulin resistance.PLoS One. 2013; 8: e59845
- Developmental origins of the metabolic syndrome: prediction, plasticity, and programming.Physiol Rev. 2005; 85: 571-633
- Developmental plasticity and human health.Nature. 2004; 430: 419-421
- Oxidative stress in development: nature or nurture.Free Radic Biol Med. 2010; 49: 1147-1151
- F(2)-isoprostanes, tocopherols and normal pregnancy.Free Radic Res. 2009; 43: 546-552
- Developmental origins of diabetes: the role of oxidative stress.Free Radic Biol Med. 2006; 40: 917-922
- Tracing the origins of fetal origins of adult diseases: programming by oxidative stress.Med Hypotheses. 2006; 66: 38-44
- The role of oxidative stress in the pathophysiology of gestational diabetes mellitus.Antioxid Redox Signal. 2011; 15: 3061-3100
- Impact of oxidative stress in fetal programming.J Pregnancy. 2012; 2012: 582748
- Release of proinflammatory cytokines and 8-isoprostane from placenta, adipose tissue, and skeletal muscle from normal pregnant women and women with gestational diabetes mellitus.J Clin Endocrinol Metab. 2004; 89: 5627-5633
- Changes in plasma lipids and markers of oxidative stress in normal pregnancy and pregnancies complicated by diabetes.Clin Sci. 2004; 106: 93-98
- Markers of oxidative stress in diabetic mothers and their infants during delivery.Physiol Res. 2005; 54: 429
- Oxidant status in maternal and cord plasma and placental tissue in gestational diabetes.Placenta. 2006; 27: 327-332
- Insulin resistance and oxidative stress in children born small and large for gestational age.Pediatrics. 2009; 124: 695-702
- Roles of melatonin in fetal programming in compromised pregnancies.Int J Mol Sci. 2013; 14: 5380-5401
- In utero oxidative stress epigenetically programs antioxidant defense capacity and adulthood diseases.Antioxid Redox Signal. 2012; 17: 237-253
- How mitochondria produce reactive oxygen species.Biochem J. 2009; 417: 1-13
- The developmental changes in mitochondrial DNA content per cell in human cord blood leukocytes during gestation.Physiol Res. 2008; 57: 947-955
- Mitochondrial DNA content and expression of genes involved in mtDNA transcription, regulation and maintenance during human fetal development.Mitochondrion. 2010; 10: 321-329
- Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction.Mitochondrion. 2013; 13: 481-492
- Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage.Aging Cell. 2004; 3: 399-411
- Mitochondrial localization of telomerase as a determinant for hydrogen peroxide-induced mitochondrial DNA damage and apoptosis.Human Mol Genet. 2006; 15: 1757-1768
- Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress.J Cell Sci. 2008; 121: 1046-1053
- Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage.Arterioscler Thromb Vasc Biol. 2009; 29: 929-935
- Molecular mechanisms involved in endothelial cell aging: role of telomerase reverse transcriptase.Zeitschrift für Gerontologie und Geriatrie. 2007; 40: 334-338
- Downregulation of mitochondrial telomerase reverse transcriptase induced by H2O2 is Src kinase dependent.Exp Gerontol. 2010; 45: 558-562
- hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells.Cancer Res. 2011; 71: 266-276
- Role of mitochondrial translocation of telomerase in hepatocellular carcinoma cells with multidrug resistance.Int J Med Sci. 2012; 9: 545-554
- Umbilical cord oxidative stress in infants of diabetic mothers and its relation to maternal hyperglycemia.J Pediatr Endocrinol Metab. 2011; 24: 671-674
- Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via Src kinase family-dependent phosphorylation of tyrosine 707.Mol Cell Biol. 2003; 23: 4598-4610
- The fetal and infant origins of adult disease.BMJ: Br Med J. 1990; 301: 1111
- Fetal programming and metabolic syndrome.Annu Rev Physiol. 2012; 74: 107-130
- Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells.Circ Res. 2004; 94: 768-775
- Human telomerase acts as a hTR-independent reverse transcriptase in mitochondria.Nucleic Acids Res. 2012; 40: 712-725
- Decreased mitochondrial DNA (mtDNA) copy number determined by real-time PCR in patients with gestational diabetes mellitus (GDM).Fertil Steril. 2004; 82: S296-S297
- Thioredoxin-1 and oxidative stress status in pregnant women at early third trimester of pregnancy: relation to maternal and neonatal characteristics.J Clin Biochem Nutr. 2013; 52: 27-31
- Lipid peroxidation in cord blood and neonatal outcome.Pediatr Int. 2006; 48: 479-483
- Oxidative stress in small-for-gestational age (SGA) term newborns and their mothers.Free Radic Res. 2009; 43: 376-384
- Oxidative stress in term small for gestational age neonates born to undernourished mothers: a case control study.BMC Pediatr. 2004; 4: 14
- Mitochondrial damage induced by conditions of oxidative stress.Free Radic Biol Med. 1999; 26: 463-471
Article info
Publication history
Published online: January 31, 2014
Accepted:
December 21,
2013
Received in revised form:
November 8,
2013
Received:
June 23,
2013
Footnotes
☆This study was supported by the national “11th Five-Year Plan” to support science and technology project grants, Ministry of Sciences and Technology, China (2009BAI80B00).
Identification
Copyright
© 2014 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
