Impact of O-GlcNAcylation Elevation on Mitophagy and Glia in the Dentate Gyrus.

O-GlcNAcylation is a dynamic and reversible protein posttranslational modification of serine or threonine residues which modulates the activity of transcriptional and signaling pathways and controls cellular responses to metabolic and inflammatory stressors. We and others have shown that O-GlcNAcylation has the potential to regulate autophagy and mitophagy to play a critical role in mitochondrial quality control, but this has not been assessed in vivo in the brain. This is important since mitochondrial dysfunction contributes to the development of neurodegenerative diseases. We used mito-QC reporter mice to assess mitophagy in diverse cells in the dentate gyrus in response to pharmacological inhibition of O-GlcNAcase (OGA) with thiamet G which leads to elevation of protein O-GlcNAcylation. We demonstrate that mitophagy occurs predominantly in the GFAP-positive astrocytes and is significantly decreased in response to elevated O-GlcNAcylation. Furthermore, with increased O-GlcNAcylation, the levels of astrocyte markers GFAP and S100B, and the microglial cell marker IBA1, decreased in the dentate gyrus, while the levels of microglial cell marker TMEM119 were increased, indicating significant changes in glia homeostasis. These results provide strong evidence of the regulation of mitophagy and glia signatures by the O-GlcNAc pathway.