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

Molecular Brain

Ji-Eun Bae¹  Dong-Hyung Cho¹  So Jung Park²  Joon Bum Kim³  Na Yeon Park³  Doo Sin Jo³  Yong-Keun Jung⁴  Dong Gyu Jo⁵  Jianguo Fang⁶ 

[1] Brain Science and Engineering Institute, Graduate School of Life Science, Kyungpook National University;Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge;Graduate School of Life Science, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University;School of Biological Sciences, Seoul National University;School of Pharmacy, Sungkyunkwan University;State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University;

关键词: Drp1;    O-GlcNAcylation;    Mitochondrial fission;    Amyloid-beta;    Alzheimer’s disease;   

DOI  :  10.1186/s13041-020-00727-w

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown