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

被引：34

作者：

Park, So Jung ^{[1
]}

Bae, Ji-Eun ^{[2
]}

Jo, Doo Sin ^{[3
]}

Kim, Joon Bum ^{[3
]}

Park, Na Yeon ^{[3
]}

Fang, Jianguo ^{[4
]}

Jung, Yong-Keun ^{[5
]}

Jo, Dong Gyu ^{[6
]}

Cho, Dong-Hyung ^{[2
,3
]}

机构：

[1] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 0XY, England

[2] Kyungpook Natl Univ, Grad Sch Life Sci, Brain Sci & Engn Inst, Daegu 41566, South Korea

[3] Kyungpook Natl Univ, Grad Sch Life Sci, BK21 FOUR KNU Creat BioRes Grp, 80 Daehakro Bukgu, Daegu 41566, South Korea

[4] Lanzhou Univ, Coll Chem & Chem Engn, State Key Lab Appl Organ Chem, Lanzhou 730000, Peoples R China

[5] Seoul Natl Univ, Sch Biol Sci, Seoul 08826, South Korea

[6] Sungkyunkwan Univ, Sch Pharm, Suwon 16419, South Korea

来源：

MOLECULAR BRAIN | 2021年 / 14卷 / 01期

基金：

新加坡国家研究基金会;

关键词：

Drp1; O-GlcNAcylation; Mitochondrial fission; Amyloid-beta; Alzheimer's disease;

D O I：

10.1186/s13041-020-00727-w

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 A beta 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 A beta-treated cells. In addition, overexpression of O-GlcNAc defective Drp1 mutant (T585A and T586A) decreased Drp1 O-GlcNAcylation and A beta-induced mitochondria fragmentation. Taken together, these finding suggest that A beta regulates mitochondrial fission by increasing O-GlcNAcylation of Drp1.

引用

页数：3

共 41 条

[41] Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid β-peptide (1-42), H2O2 and kainic acid:: implications for Alzheimer's disease
Abdul, HM
Sultana, R
Keller, JN
St Clair, DK
Markesbery, WR
Butterfield, DA
JOURNAL OF NEUROCHEMISTRY, 2006, 96 (05) : 1322 - 1335

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