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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number108579
JournalCell Reports
Volume34
Issue number1
DOIs
Publication statusPublished - 2021 Jan 5
Externally publishedYes

Keywords

  • O-GlcNAcylation
  • O-linked N-acetylglucosamine transferase
  • OGT
  • PINK1
  • hematopoietic progenitor cell
  • hematopoietic stem cell
  • mitochondria
  • mitophagy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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