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Park SJ, Bae JE, Jo DS, Kim JB, Park NY, Fang J, Jung YK, Jo DG, Cho DH. Increased O-GlcNAcylation of Drp1 by amyloid-beta promotes mitochondrial fission and dysfunction in neuronal cells. Molecular brain 2021 14(1) 33422108
Abstract:
As a dynamic organelle, mitochondria continuously fuse and divide with adjacent mitochondria. Imbalance in mitochondria dynamics leads to their dysfunction, which implicated in neurodegenerative diseases. However, how mitochondria alteration and glucose defect contribute to pathogenesis of Alzheimer's disease (AD) is still largely unknown. Dynamin-related protein 1 (Drp1) is an essential regulator for mitochondria fission. Among various posttranslational modifications, O-GlcNAcylation plays a role as a sensor for nutrient and oxidative stress. In this study, we identified that Drp1 is regulated by O-GlcNAcylation in AD models. Treatment of Aβ as well as PugNAc resulted in mitochondrial fragmentation in neuronal cells. Moreover, we found that AD mice brain exhibits an upregulated Drp1 O-GlcNAcylation. However, depletion of OGT inhibited Drp1 O-GlcNAcylation in Aβ-treated cells. In addition, overexpression of O-GlcNAc defective Drp1 mutant (T585A and T586A) decreased Drp1 O-GlcNAcylation and Aβ-induced mitochondria fragmentation. Taken together, these finding suggest that Aβ regulates mitochondrial fission by increasing O-GlcNAcylation of Drp1.
O-GlcNAc proteins:
DNM1L
Species: Rattus norvegicus
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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
Species: Rattus norvegicus, Homo sapiens, Mus musculus