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Increased O-GlcNAcylation of Drp1 by amyloid-beta promotes mitochondrial fission and dysfunction in neuronal cells.

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Park, So Jung 
Bae, Ji-Eun 
Jo, Doo Sin 
Kim, Joon Bum 
Park, Na Yeon 


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.



Alzheimer’s disease, Amyloid-beta, Drp1, Mitochondrial fission, O-GlcNAcylation, Amyloid beta-Peptides, Animals, Cells, Cultured, Dynamins, Glycosylation, Humans, Mice, Transgenic, Mitochondrial Dynamics, Neurons

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Springer Science and Business Media LLC
National Research Foundation of Korea (2020R1A2C2003523, 2017M3A9G7073521)