Regulation of mitophagy by O-linked N-acetylglucosamine transferase is essential for hematopoietic stem cell maintenance

O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) catalyzes post-translational modification of target proteins by introducing O-GlcNAc moiety on serine or threonine residues. OGT critically regulates various cellular functions in many cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) are totally unknown. Here we report critical roles of OGT in homeostasis of HSPCs. Ogt is highly expressed in HSPCs and its disruption led to their rapid loss with increased reactive oxygen species and apoptosis. In particular, Ogt-deficient HSCs lost quiescence and showed severe defects in self-renewal and long-term repopulation capacities. Interestingly, Ogt-deficient HSCs accumulated defective mitochondria due to impaired mitophagy with decreased key mitophagy regulators, Pink1 and Bnip3, through dysregulation of host cell factor 1 (HCF1)-H3K4me3 pathway, and overexpression of Pink1 rescued impaired mitophagy and numbers of Ogt-deficient HSCs. In summary, our results revealed that OGT plays an essential role in HSC maintenance by assuring mitochondrial quality through mitophagy. Overall design: Analysis of transcriptional profiles in Ogt WT and KO LSK cells