OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy

Cell Rep. 2021 Jan 5;34(1):108579. doi: 10.1016/j.celrep.2020.108579.

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.

Keywords: O-GlcNAcylation; O-linked N-acetylglucosamine transferase; OGT; PINK1; hematopoietic progenitor cell; hematopoietic stem cell; mitochondria; mitophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism
  • Animals
  • Apoptosis
  • Cell Cycle
  • Cell Line
  • Female
  • Hematopoietic Stem Cells / metabolism*
  • Histones / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Mitophagy*
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism*
  • Protein Kinases / metabolism*
  • Reactive Oxygen Species / metabolism
  • Stress, Physiological

Substances

  • Histones
  • Reactive Oxygen Species
  • histone H3 trimethyl Lys4
  • N-Acetylglucosaminyltransferases
  • Ogt protein, mouse
  • Protein Kinases
  • PTEN-induced putative kinase
  • Acetylglucosamine