Altered protein O-GlcNAcylation in placentas from mothers with diabetes causes aberrant endocytosis in placental trophoblast cells

Palin, Victoria; Russell, Matthew R.; Graham, Robert; Aplin, John D.; Westwood, Melissa

doi:10.1038/s41598-021-00045-8

Cited by 9 publications

(7 citation statements)

References 53 publications

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“…To better understand the importance of O -GlcNAc in placental tissue, a recent study documented approximately 750 O -GlcNAcylated proteins in trophoblast and fetal capillaries within the villous of the human placenta ( 32 ). Here, we show structural alterations of the placenta in SHR at 14, 17, and 20 DOP.…”

Section: Discussionmentioning

confidence: 99%

Protein O-GlcNAcylation as a nutrient sensor signaling placental dysfunction in hypertensive pregnancy

et al. 2022

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IntroductionDuring pregnancy, arterial hypertension may impair placental function, which is critical for a healthy baby's growth. Important proteins during placentation are known to be targets for O-linked β-N-acetylglucosamine modification (O-GlcNAcylation), and abnormal protein O-GlcNAcylation has been linked to pathological conditions such as hypertension. However, it is unclear how protein O-GlcNAcylation affects placental function and fetal growth throughout pregnancy during hypertension.MethodsTo investigate this question, female Wistar and spontaneously hypertensive rats (SHR) were mated with male Wistar rats, and after pregnancy confirmation by vaginal smear, rats were divided into groups of 14, 17, and 20 days of pregnancy (DOPs). On the 14th, 17th, and 20th DOP, rats were euthanized, fetal parameters were measured, and placentas were collected for western blot, immunohistochemical, and morphological analyses.ResultsSHR presented a higher blood pressure than the Wistar rats (p=0.001). Across all DOPs, SHR showed reduced fetal weight and an increase in small-for-gestational-age fetuses. While near-term placentas were heavier in SHR (p=0.006), placental efficiency decreased at 17 (p=0.01) and 20 DOPs (p<0.0001) in this group. Morphological analysis revealed reduced junctional zone area and labyrinth vasculature changes on SHR placentas in all DOPs. O-GlcNAc protein expression was lower in placentas from SHR compared with Wistar at 14, 17, and 20 DOPs. Decreased expression of O-GlcNAc transferase (p=0.01) and O-GlcNAcase (p=0.002) enzymes was found at 14 DOPs in SHR. Immunohistochemistry showed reduced placental O-GlcNAc content in both the junctional zone and labyrinth of the placentas from SHR. Periodic acid-Schiff analysis showed decreased glycogen cell content in the placentas from SHR at 14, 17, and 20 DOPs. Moreover, glucose transporter 1 expression was decreased in placentas from SHR in all DOPs.ConclusionsThese findings suggest that decreased protein O-GlcNAcylation caused by insufficient placental nutritional apport contributes to placental dysfunction during hypertensive pregnancy, impairing fetal growth.

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Section: Discussionmentioning

confidence: 99%

Protein O-GlcNAcylation as a nutrient sensor signaling placental dysfunction in hypertensive pregnancy

et al. 2022

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“…Thus, serine plays an important role in nucleotide synthesis, methylation reactions, and glutathione synthesis 12,14 . The blocking or abnormality of these pathways may impair decidualization and implantation, interfere with trophoblastic function, and affect embryonic growth and development 15,16 …”

Section: A Brief Overview Of Glycolysismentioning

confidence: 99%

Glycolysis: A fork in the path of normal and pathological pregnancy

Gou,

Zhang

2023

The FASEB Journal

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Glucose metabolism is vital to the survival of living organisms. Since the discovery of the Warburg effect in the 1920s, glycolysis has become a major research area in the field of metabolism. Glycolysis has been extensively studied in the field of cancer and is considered as a promising therapeutic target. However, research on the role of glycolysis in pregnancy is limited. Recent evidence suggests that blastocysts, trophoblasts, decidua, and tumors all acquire metabolic energy at specific stages in a highly similar manner. Glycolysis, carefully controlled throughout pregnancy, maintains a dynamic and coordinated state, so as to maintain the homeostasis of the maternal–fetal interface and ensure normal gestation. In the present review, we investigate metabolic remodeling and the selective propensity of the embryo and placenta for glycolysis. We then address dysregulated glycolysis that occurs in the cellular interactive network at the maternal–fetal interface in miscarriage, preeclampsia, fetal growth restriction, and gestational diabetes mellitus. We provide new insights into the field of maternal–fetal medicine from a metabolic perspective, thus revealing the mystery of human pregnancy.

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“…Clathrin light chain B (LCB) is O-GlcNAcylated in its C-terminal region, at S217/S221 [98], while Clathrin heavy chain 1 (CHC1) is O-GlcNAcylated at S97 which is located within a clathrin box motif (CMB) involved in AP2 binding [99] (Table 2). However, to date, the functional relevance of O-GlcNAc PTM on clathrin chains is fully unknown.…”

Section: O-glcnacylation Of Clathrin and Endocytic Accessory Proteinsmentioning

confidence: 99%

“…Palin and colleagues explored the O-GlcNAcome of placentas from diabetic mothers. They showed that many proteins involved in CME, such as CHC, AP2A2, and Dyn2 are abnormally O-GlcNAcylated in diabetic tissue compared to the control groups [98]. Thus, in addition to phosphorylation-dependent signaling pathways that are crucial to adapt the endocytosis rate to the nutrient uptake and metabolic status of the cell [20], a role for the nutrient-sensing O-GlcNAc modification in the regulation of clathrin-dependent endocytic traffic has emerged.…”

Section: O-glcnacylation Of Clathrin and Endocytic Accessory Proteinsmentioning

confidence: 99%

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O-GlcNAc Dynamics: The Sweet Side of Protein Trafficking Regulation in Mammalian Cells

Ahmed

Lemaire

Scache

et al. 2023

Cells

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The transport of proteins between the different cellular compartments and the cell surface is governed by the secretory pathway. Alternatively, unconventional secretion pathways have been described in mammalian cells, especially through multivesicular bodies and exosomes. These highly sophisticated biological processes rely on a wide variety of signaling and regulatory proteins that act sequentially and in a well-orchestrated manner to ensure the proper delivery of cargoes to their final destination. By modifying numerous proteins involved in the regulation of vesicular trafficking, post-translational modifications (PTMs) participate in the tight regulation of cargo transport in response to extracellular stimuli such as nutrient availability and stress. Among the PTMs, O-GlcNAcylation is the reversible addition of a single N-acetylglucosamine monosaccharide (GlcNAc) on serine or threonine residues of cytosolic, nuclear, and mitochondrial proteins. O-GlcNAc cycling is mediated by a single couple of enzymes: the O-GlcNAc transferase (OGT) which catalyzes the addition of O-GlcNAc onto proteins, and the O-GlcNAcase (OGA) which hydrolyses it. Here, we review the current knowledge on the emerging role of O-GlcNAc modification in the regulation of protein trafficking in mammalian cells, in classical and unconventional secretory pathways.

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Altered protein O-GlcNAcylation in placentas from mothers with diabetes causes aberrant endocytosis in placental trophoblast cells

Cited by 9 publications

References 53 publications

Protein O-GlcNAcylation as a nutrient sensor signaling placental dysfunction in hypertensive pregnancy

Protein O-GlcNAcylation as a nutrient sensor signaling placental dysfunction in hypertensive pregnancy

Glycolysis: A fork in the path of normal and pathological pregnancy

O-GlcNAc Dynamics: The Sweet Side of Protein Trafficking Regulation in Mammalian Cells

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