Sustained O-GlcNAcylation reprograms mitochondrial function to regulate energy metabolism

Tan, Ee Phie; McGreal, Steven R.; Graw, Stefan; Tessman, Robert; Koppel, Scott J.; Dhakal, Pramod; Zhang, Zhen; Machacek, Miranda; Zachara, Natasha E.; Koestler, Devin C.; Peterson, Kenneth R.; Thyfault, John P.; Swerdlow, Russell H.; Krishnamurthy, Partha; DiTacchio, Luciano; Apte, Udayan; Slawson, Chad

doi:10.1074/jbc.m117.797944

Cited by 91 publications

(102 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Zhao et al reviewed the regulatory roles of OGT in mitochondria (Zhao et al 2016). Recent findings have demonstrated that O-GlcNAcylation is widely spread among mitochondrial proteins and that mitochondrial function and oxidative stress both can be regulated by O-GlcNAcylation (Tan et al 2017). The role of OGT in placental mitochondria is under studied and warrants further investigation.…”

Section: Oxidative Stressmentioning

confidence: 99%

Nutrient sensor signaling pathways and cellular stress in fetal growth restriction

Hart

Morgan

Alejandro

2019

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Fetal growth restriction is one of the most common obstetrical complications resulting in significant perinatal morbidity and mortality. The most frequent etiology of human singleton fetal growth restriction is placental insufficiency, which occurs secondary to reduced utero-placental perfusion, abnormal placentation, impaired trophoblast invasion and spiral artery remodeling, resulting in altered nutrient and oxygen transport. Two nutrient-sensing proteins involved in placental development and glucose and amino acid transport are mechanistic target of rapamycin (mTOR) and O-linked N-acetylglucosamine transferase (OGT), which are both regulated by availability of oxygen. Impairment in either of these pathways is associated with fetal growth restriction and accompanied by cellular stress in the forms of hypoxia, oxidative and endoplasmic reticulum (ER) stress, metabolic dysfunction and nutrient starvation in the placenta. Recent evidence has emerged regarding the potential impact of nutrient sensors on fetal stress response, which occurs in a sexual dysmorphic manner, indicating a potential element of genetic gender susceptibility to fetal growth restriction. In this mini review, we focus on the known role of mTOR and OGT in placental development, nutrient regulation and response to cellular stress in human fetal growth restriction with supporting evidence from rodent models.

show abstract

Section: Oxidative Stressmentioning

confidence: 99%

Nutrient sensor signaling pathways and cellular stress in fetal growth restriction

Hart

Morgan

Alejandro

2019

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

show abstract

“…Our approach to measure both the open and closed sites for O-GlcNAc in theory allows us to determine this parameter for O-GlcNAcylation of a biological sample. Since O-GlcNAc regulates the energy metabolism (Tan et al, 2017) and dysregulation of O-GlcNAcylation correlates to insulin resistance in diabetes (Ma and Hart, 2013;Wollaston-Hayden et al, 2014) and tumorigenesis (Ferrer et al, 2016;Hanover et al, 2018), modification degree of O-GlcNAc could be a useful index of metabolic status and may be used for diagnosis and prognosis of cancer and diabetes.…”

Section: Figure 2 B3galnt2 Adds a Galnac Residue To O-glcnacylated Cmentioning

confidence: 99%

Detecting and Imaging O-GlcNAc Sites Using Glycosyltransferases: A Systematic Approach to Study O-GlcNAc

Tatge

Grill

et al. 2018

Cell Chemical Biology

View full text Add to dashboard Cite

O-GlcNAcylation is a reversible serine/threonine glycosylation for regulating protein activity and availability inside cells. In a given protein, O-GlcNAcylated and unoccupied O-linked β-N-acetylglucosamine (O-GlcNAc) sites are referred to as closed and open sites, respectively. The balance between open and closed sites is believed to be dynamically regulated. In this report, closed sites are detected using in vitro incorporation of GalNAz by B3GALNT2, and open sites are detected by in vitro incorporation of GlcNAz by O-GlcNAc transferase (OGT), via click chemistry. For assessing total O-GlcNAc sites, a sample is O-GlcNAcylated in vitro by OGT before detecting by B3GALNT2. The methods are demonstrated on purified recombinant proteins including CK2, AKT1, and PFKFB3, and cellular extracts of HEK cells. Through O-GlcNAc imaging, the modification degree of O-GlcNAc in nuclei of Chinese hamster ovary cells was estimated. The detection and imaging of both open and closed O-GlcNAc sites provide a systematic approach to study this important post-translational modification.

show abstract

“…Furthermore, reducing OGT expression in liver tissue impairs mitochondrial function, and alters ROS production and antioxidant signalling (Tan et al . ). Thus it is possible that some of the sex specific effects identified in the current study may be due to the gene dosage of OGT in mouse placental tissue.…”

Section: Discussionmentioning

confidence: 97%

“…Interestingly, when OGT is deleted from the placenta, mitochondrial dysfunction occurs in the hypothalamus of offspring (Howerton & Bale, 2014). Furthermore, reducing OGT expression in liver tissue impairs mitochondrial function, and alters ROS production and antioxidant signalling (Tan et al 2017). Thus it is possible that some of the sex specific effects identified in the current study may be due to the gene dosage of OGT in mouse placental tissue.…”

Section: Effects Of Corticosterone On Mitochondrial Functionmentioning

confidence: 88%

Maternal corticosterone in the mouse alters oxidative stress markers, antioxidant function and mitochondrial content in placentas of female fetuses

Bartho

Holland

Moritz

et al. 2019

The Journal of Physiology

View full text Add to dashboard Cite

Key points Maternal exposure to the stress hormone corticosterone is known to programme a range of sex specific disease outcomes in offspring. Sex differences in placental adaptations are thought to mediate these processes. Placental oxidative stress is implicated in a range of pregnancy disorders but the role of placental oxidative stress in sex specific disease outcomes following prenatal corticosterone exposure is unknown. This study demonstrates that maternal corticosterone reduced placental hydrogen peroxide and 8‐hydroxy‐2′‐deoxyguanosine concentrations but increased protein carbonyl content and advanced glycation end product concentrations in placentas of female fetuses but not male fetuses. These results highlight that placentas of female fetuses respond differently to maternal corticosterone exposure, with oxidative stress a major finding in placentas of female fetuses. Abstract Maternal exposure to glucocorticoids during pregnancy increases offspring risk of developing a range of sex specific disease phenotypes. These sex specific disease outcomes are thought to be in part mediated by different placental adaptations in males and females. The placenta is a highly metabolic organ which is vulnerable to the effects of oxidative stress. In other tissues, males and females have been shown to respond differently to the pro‐oxidant effects of glucocorticoids. This study therefore used a well characterized animal model of maternal corticosterone exposure to investigate sex specific alterations in reactive oxygen species production, antioxidant concentrations and mitochondrial properties that might contribute to sex differences in placental outcomes. C57BL/6 mice were implanted with osmotic minipumps containing corticosterone (33 μg kg−1 h−1) at embryonic day (E) 12.5 and placentas collected at E14.5 for analysis. Corticosterone exposure reduced placental hydrogen peroxide (H2O2) and 8‐hydroxy‐2′‐deoxyguanosine concentrations but increased protein carbonyl content and advanced glycation end product concentrations in placentas of female fetuses but not male fetuses. This dysregulation of different markers of oxidative stress may be due to increased placental activity of thioredoxin reductase in female but not male fetuses. Corticosterone reduced placental mitochondrial content but increased protein expression of the autophagosome cargo protein p62. This study demonstrates that placentas of female fetuses respond differently to maternal corticosterone exposure and highlights an important role of reactive oxygen species, mitochondrial adaptations and antioxidant responses in glucocorticoid induced programmed disease.

show abstract

Sustained O-GlcNAcylation reprograms mitochondrial function to regulate energy metabolism

Cited by 91 publications

References 62 publications

Nutrient sensor signaling pathways and cellular stress in fetal growth restriction

Nutrient sensor signaling pathways and cellular stress in fetal growth restriction

Detecting and Imaging O-GlcNAc Sites Using Glycosyltransferases: A Systematic Approach to Study O-GlcNAc

Maternal corticosterone in the mouse alters oxidative stress markers, antioxidant function and mitochondrial content in placentas of female fetuses

Contact Info

Product

Resources

About