OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy

被引：35

作者：

Murakami, Koichi ^{[1
,2
,3
]}

Kurotaki, Daisuke ^{[4
]}

Kawase, Wataru ^{[4
]}

Soma, Shunsuke ^{[1
]}

Fukuchi, Yumi ^{[1
]}

Kunimoto, Hiroyoshi ^{[2
]}

Yoshimi, Ryusuke ^{[2
]}

Koide, Shuhei ^{[5
,6
]}

Oshima, Motohiko ^{[5
,6
]}

Hishiki, Takako ^{[7
,8
]}

Hayakawa, Noriyo ^{[7
]}

Matsuura, Tomomi ^{[7
]}

Oda, Mayumi ^{[9
]}

Yanagisawa, Kiichi ^{[10
]}

Kobayashi, Hiroshi ^{[10
]}

Haraguchi, Miho ^{[10
]}

Atobe, Yoshitoshi ^{[11
]}

Funakoshi, Kengo ^{[11
]}

Iwama, Atsushi ^{[5
,6
]}

Takubo, Keiyo ^{[10
]}

Okamoto, Shinichiro ^{[1
]}

Tamura, Tomohiko ^{[3
,4
]}

Nakajima, Hideaki ^{[2
]}

机构：

[1] Keio Univ, Dept Internal Med, Div Hematol, Sch Med, Tokyo 1608582, Japan

[2] Yokohama City Univ, Dept Stem Cell & Immune Regulat, Grad Sch Med, Yokohama, Kanagawa 2360004, Japan

[3] Yokohama City Univ, Adv Med Res Ctr, Yokohama, Kanagawa 2360004, Japan

[4] Yokohama City Univ, Dept Immunol, Grad Sch Med, Yokohama, Kanagawa 2360004, Japan

[5] Chiba Univ, Grad Sch Med, Dept Cellular & Mol Med, Chiba 2608670, Japan

[6] Univ Tokyo, Ctr Stem Cell Biol & Regenerat Med, Inst Med Sci, Div Stem Cell & Mol Med, Tokyo 1088039, Japan

[7] Keio Univ, Clin & Translat Res Ctr, Sch Med, Tokyo 1608582, Japan

[8] Keio Univ, Dept Biochem, Sch Med, Tokyo 1608582, Japan

[9] Keio Univ, Dept Syst Med, Sch Med, Tokyo 1608582, Japan

[10] Natl Ctr Global Hlth & Med, Res Inst, Dept Stem Cell Biol, Tokyo 1628655, Japan

[11] Yokohama City Univ, Dept Neuroanat, Sch Med, Yokohama, Kanagawa 2360004, Japan

来源：

CELL REPORTS | 2021年 / 34卷 / 01期

关键词：

O-GLCNAC TRANSFERASE; DAMAGED MITOCHONDRIA; METABOLIC-REGULATION; TRANSCRIPTION FACTOR; SELF-RENEWAL; GLCNACYLATION; QUIESCENCE; AUTOPHAGY; PINK1; METHYLATION;

D O I：

10.1016/j.celrep.2020.108579

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogtdeficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.

引用

页数：21

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