Mitol dysfunction triggers apoptosis of hematopoietic stem cell via ER stress response

Cellular metabolism exceedingly determines hematopoietic stem cells (HSCs) divisional fate and functioning through organelles interaction upon stress-induced response. The outer mitochondrial membrane-localized E3 ubiquitin ligase Mitol/Marchf5 (encoded by Mitol gene) is known to regulate mitochondrial and endoplasmic reticulum (ER) interaction and promote cell survival. To investigate the precise functional involvement of Mitol in HSC maintenance, we analyzed MX1-cre inducible Mitol knockout mice. Mitol deletion in bone marrow (BM) leads to HSCs exhaustion and impairment of BM reconstitution capability. Moreover, Mitol deletion induced prolonged ER stress in HSCs, which triggers cellular apoptosis that is mainly regulated by IRE1a signaling. Inhibition of ER stress by KIRA6 could partially reduce apoptosis of long term-HSC. Our observations indicated that Mitol is principal to maintain hematopoietic homeostasis and protects HSCs from apoptosis mainly through ER function via IRE1a signaling. HSC fraction (CD150+ CD48- EPCR+ Lineage-) were sorted from bone marrow of control and Mitol knockout (KO) mice, and subsequently mRNA profiles were generated by deep sequencing using Next-seq.