OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy

Koichi Murakami, Daisuke Kurotaki, Wataru Kawase, Shunsuke Soma, Yumi Fukuchi, Hiroyoshi Kunimoto, Ryusuke Yoshimi, Shuhei Koide, Motohiko Oshima, Takako Hishiki, Noriyo Hayakawa, Tomomi Matsuura, Mayumi Oda, Kiichi Yanagisawa, Hiroshi Kobayashi, Miho Haraguchi, Yoshitoshi Atobe, Kengo Funakoshi, Atsushi Iwama, Keiyo TakuboShinichiro Okamoto, Tomohiko Tamura, Hideaki Nakajima

研究成果: Article査読

4 被引用数 (Scopus)

抄録

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, Ogt-deficient 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.

本文言語English
論文番号108579
ジャーナルCell Reports
34
1
DOI
出版ステータスPublished - 2021 1 5

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)

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