Mitochondrial Protein Synthesis Is Essential for Terminal Differentiation of CD45– TER119–Erythroid and Lymphoid Progenitors
Kazuhito Gotoh,
Yuya Kunisaki,
Soichi Mizuguchi,
Daiki Setoyama,
Kentaro Hosokawa,
Hisayuki Yao,
Yuya Nakashima,
Mikako Yagi,
Takeshi Uchiumi,
Yuichiro Semba,
Jumpei Nogami,
Koichi Akashi,
Fumio Arai,
Dongchon Kang
Affiliations
Kazuhito Gotoh
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Corresponding author
Yuya Kunisaki
Department of Stem Cell Biology and Medicine/Cancer Stem Cell Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Medicine and Biosystemic Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan; Corresponding author
Soichi Mizuguchi
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Daiki Setoyama
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Kentaro Hosokawa
Department of Stem Cell Biology and Medicine/Cancer Stem Cell Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Hisayuki Yao
Department of Stem Cell Biology and Medicine/Cancer Stem Cell Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Yuya Nakashima
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Mikako Yagi
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Health Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Takeshi Uchiumi
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Health Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Yuichiro Semba
Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan
Jumpei Nogami
Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan
Koichi Akashi
Department of Medicine and Biosystemic Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Fumio Arai
Department of Stem Cell Biology and Medicine/Cancer Stem Cell Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Dongchon Kang
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Corresponding author
Summary: p32/C1qbp regulates mitochondrial protein synthesis and is essential for oxidative phosphorylation in mitochondria. Although dysfunction of p32/C1qbp impairs fetal development and immune responses, its role in hematopoietic differentiation remains unclear. Here, we found that mitochondrial dysfunction affected terminal differentiation of newly identified erythroid/B-lymphoid progenitors among CD45– Ter119– CD31– triple-negative cells (TNCs) in bone marrow. Hematopoietic cell-specific genetic deletion of p32/C1qbp (p32cKO) in mice caused anemia and B-lymphopenia without reduction of hematopoietic stem/progenitor cells. In addition, p32cKO mice were susceptible to hematopoietic stress with delayed recovery from anemia. p32/C1qbp-deficient CD51– TNCs exhibited impaired mitochondrial oxidation that consequently led to inactivation of mTORC1 signaling, which is essential for erythropoiesis. These findings uncover the importance of mitochondria, especially at the stage of TNCs during erythropoiesis, suggesting that dysregulation of mitochondrial protein synthesis is a cause of anemia and B-lymphopenia with an unknown pathology.
