MITOL deficiency triggers hematopoietic stem cell apoptosis via ER stress response

Hematopoietic stem cell (HSC) divisional fate and function are determined by cellular metabolism, yet the contribution of specific cellular organelles and metabolic pathways to blood maintenance and stress-induced responses in the bone marrow remains poorly understood. The outer mitochondrial membrane-localized E3 ubiquitin ligase MITOL/MARCHF5 (encoded by the Mitol gene) is known to regulate mitochondrial and endoplasmic reticulum (ER) interaction and to promote cell survival. Here, we investigated the functional involvement of MITOL in HSC maintenance by generating MX1-cre inducible Mitol knockout mice. MITOL deletion in the bone marrow resulted in HSC exhaustion and impairment of bone marrow reconstitution capability in vivo. Interestingly, MITOL loss did not induce major mitochondrial dysfunction in hematopoietic stem and progenitor cells. In contrast, MITOL deletion induced prolonged ER stress in HSCs, which triggered cellular apoptosis regulated by IRE1α. In line, dampening of ER stress signaling by IRE1α inihibitor KIRA6 partially rescued apoptosis of long-term-reconstituting HSC. In summary, our observations indicate that MITOL is a principal regulator of hematopoietic homeostasis and protects blood stem cells from cell death through its function in ER stress signaling. Synopsis Metabolic control of hematopoietic stem cell (HSC) function in blood maintenance remains poorly understood. Here, genetic work reports mitochondrial ubiquitin ligase MITOL (also known as MARCHF5) as a factor required for HSC survival and hematopoietic homeostasis in mice via suppression of ER stress signaling. MITOL deletion in the bone marrow causes HSC exhaustion and failure of blood reconstitution post engraftment. MITOL deletion induces unresolved ER stress in HSCs but only minor mitochondrial dysfunction. MITOL deletion induces ER stress-mediated apoptosis in HSCs via IRE1α-XBP1 signaling. IRE1α inhibition partially rescues Mitol deletion-induced apoptosis of HSCs. Mitochondrial E3 ubiquitin ligase MITOL is a critical regulator of blood stem cell survival and bone marrow reconstitution capability.