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Zhao J, Dong L, Huo T, Cheng J, Li X, Huangfu X, Sun S, Wang H, Li L. O-GlcNAc Transferase (OGT) Protects Cerebral Neurons from Death During Ischemia/Reperfusion (I/R) Injury by Modulating Drp1 in Mice. Neuromolecular medicine 2022 24(3) 34705256
Abstract:
Previous studies have demonstrated that increased O-linked N-acetylglucosamine (O-GlcNAc) level could promote cell survival following environmental stresses. This study aimed to explore the role of O-GlcNAc transferase (OGT) during cerebral ischemia/reperfusion (I/R) injury. The mouse model with cerebral I/R injury was induced by middle cerebral artery occlusion/reperfusion (MCAO/R). The expression of ogt in brain tissues was detected by qRT-PCR, Western blot, and immunohistochemistry (IHC) staining assay. Neurological deficit was evaluated using a modified scoring system. The infarct volume was assessed by TTC staining assay. Neuronal apoptosis in brain tissues was evaluated by TUNEL staining assay. The level of cleaved caspase-3 in brain tissues was detected by Western blot and IHC staining assay. The expression of critical proteins involved in mitochondrial fission, including OPA1, Mfn1, and Mfn2, as well as Mff and Drp1 was detected by Western blot and IHC, respectively. The expression of ogt during cerebral I/R injury was significantly upregulated. Ogt knockdown significantly increased neurological score and infarct volume in I/R-induced mice. Meanwhile, ogt knockdown significantly enhanced neuronal apoptosis and cleaved caspase-3 level in brain tissues of I/R-induced mice. In addition, ogt knockdown markedly decreased serine 637 phosphorylation level of mitochondrial fission protein dynamin-related protein 1 (Drp1) and promoted Drp1 translocation from the cytosol to the mitochondria. Moreover, the specific Drp1 inhibitor mdivi-1 effectively attenuated ogt knockdown-induced brain injury of I/R-stimulated mice in vivo. Our study revealed that OGT protects against cerebral I/R injury by inhibiting the function of Drp1 in mice, suggesting that ogt may be a potential therapeutic target for cerebral I/R injury.
O-GlcNAc proteins:
DNM1L
Species: Mus musculus
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Akinbiyi EO, Abramowitz LK, Bauer BL, Stoll MSK, Hoppel CL, Hsiao CP, Hanover JA, Mears JA. Blocked O-GlcNAc cycling alters mitochondrial morphology, function, and mass. Scientific reports 2021 11(1) 34764359
Abstract:
O-GlcNAcylation is a prevalent form of glycosylation that regulates proteins within the cytosol, nucleus, and mitochondria. The O-GlcNAc modification can affect protein cellular localization, function, and signaling interactions. The specific impact of O-GlcNAcylation on mitochondrial morphology and function has been elusive. In this manuscript, the role of O-GlcNAcylation on mitochondrial fission, oxidative phosphorylation (Oxphos), and the activity of electron transport chain (ETC) complexes were evaluated. In a cellular environment with hyper O-GlcNAcylation due to the deletion of O-GlcNAcase (OGA), mitochondria showed a dramatic reduction in size and a corresponding increase in number and total mitochondrial mass. Because of the increased mitochondrial content, OGA knockout cells exhibited comparable coupled mitochondrial Oxphos and ATP levels when compared to WT cells. However, we observed reduced protein levels for complex I and II when comparing normalized mitochondrial content and reduced linked activity for complexes I and III when examining individual ETC complex activities. In assessing mitochondrial fission, we observed increased amounts of O-GlcNAcylated dynamin-related protein 1 (Drp1) in cells genetically null for OGA and in glioblastoma cells. Individual regions of Drp1 were evaluated for O-GlcNAc modifications, and we found that this post-translational modification (PTM) was not limited to the previously characterized residues in the variable domain (VD). Additional modification sites are predicted in the GTPase domain, which may influence enzyme activity. Collectively, these results highlight the impact of O-GlcNAcylation on mitochondrial dynamics and ETC function and mimic the changes that may occur during glucose toxicity from hyperglycemia.
O-GlcNAc proteins:
DNM1L, DNM1L, DNM1L
Lee BE, Kim HY, Kim HJ, Jeong H, Kim BG, Lee HE, Lee J, Kim HB, Lee SE, Yang YR, Yi EC, Hanover JA, Myung K, Suh PG, Kwon T, Kim JI. O-GlcNAcylation regulates dopamine neuron function, survival and degeneration in Parkinson disease. Brain : a journal of neurology 2020 143(12) 33300544
Abstract:
The dopamine system in the midbrain is essential for volitional movement, action selection, and reward-related learning. Despite its versatile roles, it contains only a small set of neurons in the brainstem. These dopamine neurons are especially susceptible to Parkinson's disease and prematurely degenerate in the course of disease progression, while the discovery of new therapeutic interventions has been disappointingly unsuccessful. Here, we show that O-GlcNAcylation, an essential post-translational modification in various types of cells, is critical for the physiological function and survival of dopamine neurons. Bidirectional modulation of O-GlcNAcylation importantly regulates dopamine neurons at the molecular, synaptic, cellular, and behavioural levels. Remarkably, genetic and pharmacological upregulation of O-GlcNAcylation mitigates neurodegeneration, synaptic impairments, and motor deficits in an animal model of Parkinson's disease. These findings provide insights into the functional importance of O-GlcNAcylation in the dopamine system, which may be utilized to protect dopamine neurons against Parkinson's disease pathology.