OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy

• Published in: Cell reports (Cambridge) 2021-01, Vol.34 (1), p.108579-108579, Article 108579
• Main Authors: Murakami, Koichi, Kurotaki, Daisuke, Kawase, Wataru, Soma, Shunsuke, Fukuchi, Yumi, Kunimoto, Hiroyoshi, Yoshimi, Ryusuke, Koide, Shuhei, Oshima, Motohiko, Hishiki, Takako, Hayakawa, Noriyo, Matsuura, Tomomi, Oda, Mayumi, Yanagisawa, Kiichi, Kobayashi, Hiroshi, Haraguchi, Miho, Atobe, Yoshitoshi, Funakoshi, Kengo, Iwama, Atsushi, Takubo, Keiyo, Okamoto, Shinichiro, Tamura, Tomohiko, Nakajima, Hideaki
• Format: Article
• Language: English
• Subjects: hematopoietic progenitor cell; hematopoietic stem cell; mitochondria; mitophagy; O-GlcNAcylation; O-linked N-acetylglucosamine transferase; OGT; PINK1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108579

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. [Display omitted] •Ogt is highly expressed in HSPCs, and cellular O-GlcNAc level is the highest in HSCs•OGT disruption in HSCs leads to rapid loss of HSPCs with increased ROS and apoptosis•Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy•OGT ensures mitochondrial quality through PINK1-dependent mitophagy in HSCs O-GlcNAcylation is an essential post-translational modification mediated by O-GlcNAc transferase (OGT). Murakami et al. demonstrate that OGT is required for stress response and maintenance of hematopoietic stem cells (HSCs). Mechanistically, quality control of mitochondria through OGT-mediated PINK1-dependent mitophagy is critical for maintaining HSCs competent for energy demands during stress.