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Yang L, Tang H, Wang J, Xu D, Xuan R, Xie S, Xu P, Li X. O-GlcNAcylation attenuates ischemia-reperfusion-induced pulmonary epithelial cell ferroptosis via the Nrf2/G6PDH pathway. BMC biology 2025 23(1) 39901237
Abstract:
Lung ischemia-reperfusion (I/R) injury is a common clinical pathology associated with high mortality. The pathophysiology of lung I/R injury involves ferroptosis and elevated protein O-GlcNAcylation levels, while the effect of O-GlcNAcylation on lung I/R injury remains unclear. This research aimed to explore the effect of O-GlcNAcylation on reducing ferroptosis in pulmonary epithelial cells caused by I/R.
O-GlcNAc proteins:
NF2L2, NF2L2
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Costa RM, Dias MC, Alves JV, Silva JLM, Rodrigues D, Silva JF, Francescato HDC, Ramalho LNZ, Coimbra TM, Tostes RC. Pharmacological activation of nuclear factor erythroid 2-related factor-2 prevents hyperglycemia-induced renal oxidative damage: Possible involvement of O-GlcNAcylation. Biochemical pharmacology 2024 220 38097051
Abstract:
Hyperglycemia is a major risk factor for kidney diseases. Oxidative stress, caused by reactive oxygen species, is a key factor in the development of kidney abnormalities related to hyperglycemia. The nuclear factor erythroid 2-related factor-2 (Nrf2) plays a crucial role in defending cells against oxidative stress by activating genes that produce antioxidants. L-sulforaphane (SFN), a drug that activates Nrf2, reduces damage caused by hyperglycemia. Hyperglycemic Wistar rats and HEK 293 cells maintained in hyperglycemic medium exhibited decreased Nrf2 nuclear translocation and reduced expression and activity of antioxidant enzymes. SFN treatment increased Nrf2 activity and reversed decreased renal function, oxidative stress and cell death associated with hyperglycemia. To investigate mechanisms involved in hyperglycemia-induced reduced Nrf2 activity, we addressed whether Nrf2 is modified by O-linked β-N-acetylglucosamine (O-GlcNAc), a post-translational modification that is fueled in hyperglycemic conditions. In vivo, hyperglycemia increased O-GlcNAc-modified Nrf2 expression. Increased O-GlcNAc levels, induced by pharmacological inhibition of OGA, decreased Nrf2 activity in HEK 293 cells. In conclusion, hyperglycemia reduces Nrf2 activity, promoting oxidative stress, cell apoptosis and structural and functional renal damage. Pharmacological treatment with SFN attenuates renal injury. O-GlcNAcylation negatively modulates Nrf2 activity and represents a potential mechanism leading to oxidative stress and renal damage in hyperglycemic conditions.
O-GlcNAc proteins:
NF2L2
Species: Homo sapiens
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Zhang Y, Sun C, Ma L, Xiao G, Gu Y, Yu W. O-GlcNAcylation promotes malignancy and cisplatin resistance of lung cancer by stabilising NRF2. Clinical and translational medicine 2024 14(10) 39358921
Abstract:
The transcription factor NRF2 plays a significant role in regulating genes that protect cells from oxidative damage. O-GlcNAc modification, a type of posttranslational modification, is crucial for cellular response to stress. Although the involvement of both NRF2 and O-GlcNAc in maintaining cellular redox balance and promoting cancer malignancy has been demonstrated, the potential mechanisms remain elusive.
O-GlcNAc proteins:
NF2L2
Species: Homo sapiens
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Tan EP, McGreal SR, Graw S, Tessman R, Koppel SJ, Dhakal P, Zhang Z, Machacek M, Zachara NE, Koestler DC, Peterson KR, Thyfault JP, Swerdlow RH, Krishnamurthy P, DiTacchio L, Apte U, Slawson C. Sustained O-GlcNAcylation reprograms mitochondrial function to regulate energy metabolism. The Journal of biological chemistry 2017 292(36) 28739801
Abstract:
Dysfunctional mitochondria and generation of reactive oxygen species (ROS) promote chronic diseases, which have spurred interest in the molecular mechanisms underlying these conditions. Previously, we have demonstrated that disruption of post-translational modification of proteins with β-linked N-acetylglucosamine (O-GlcNAcylation) via overexpression of the O-GlcNAc-regulating enzymes O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) impairs mitochondrial function. Here, we report that sustained alterations in O-GlcNAcylation either by pharmacological or genetic manipulation also alter metabolic function. Sustained O-GlcNAc elevation in SH-SY5Y neuroblastoma cells increased OGA expression and reduced cellular respiration and ROS generation. Cells with elevated O-GlcNAc levels had elongated mitochondria and increased mitochondrial membrane potential, and RNA-sequencing analysis indicated transcriptome reprogramming and down-regulation of the NRF2-mediated antioxidant response. Sustained O-GlcNAcylation in mouse brain and liver validated the metabolic phenotypes observed in the cells, and OGT knockdown in the liver elevated ROS levels, impaired respiration, and increased the NRF2 antioxidant response. Moreover, elevated O-GlcNAc levels promoted weight loss and lowered respiration in mice and skewed the mice toward carbohydrate-dependent metabolism as determined by indirect calorimetry. In summary, sustained elevation in O-GlcNAcylation coupled with increased OGA expression reprograms energy metabolism, a finding that has potential implications for the etiology, development, and management of metabolic diseases.
O-GlcNAc proteins:
NF2L2
Species: Homo sapiens
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