TY - JOUR
T1 - OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy
AU - Murakami, Koichi
AU - Kurotaki, Daisuke
AU - Kawase, Wataru
AU - Soma, Shunsuke
AU - Fukuchi, Yumi
AU - Kunimoto, Hiroyoshi
AU - Yoshimi, Ryusuke
AU - Koide, Shuhei
AU - Oshima, Motohiko
AU - Hishiki, Takako
AU - Hayakawa, Noriyo
AU - Matsuura, Tomomi
AU - Oda, Mayumi
AU - Yanagisawa, Kiichi
AU - Kobayashi, Hiroshi
AU - Haraguchi, Miho
AU - Atobe, Yoshitoshi
AU - Funakoshi, Kengo
AU - Iwama, Atsushi
AU - Takubo, Keiyo
AU - Okamoto, Shinichiro
AU - Tamura, Tomohiko
AU - Nakajima, Hideaki
N1 - Publisher Copyright:
© 2020 The Author(s)
PY - 2021/1/5
Y1 - 2021/1/5
N2 - 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.
AB - 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.
KW - O-GlcNAcylation
KW - O-linked N-acetylglucosamine transferase
KW - OGT
KW - PINK1
KW - hematopoietic progenitor cell
KW - hematopoietic stem cell
KW - mitochondria
KW - mitophagy
UR - http://www.scopus.com/inward/record.url?scp=85099225028&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099225028&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2020.108579
DO - 10.1016/j.celrep.2020.108579
M3 - Article
C2 - 33406421
AN - SCOPUS:85099225028
SN - 2211-1247
VL - 34
JO - Cell Reports
JF - Cell Reports
IS - 1
M1 - 108579
ER -