Disruption of mitochondrial energy metabolism is a putative pathogenesis of Diamond-Blackfan anemia
Rudan Xiao,
Lijuan Zhang,
Zijuan Xin,
Junwei Zhu,
Qian Zhang,
Guangmin Zheng,
Siyun Chu,
Jing Wu,
Lu Zhang,
Yang Wan,
Xiaojuan Chen,
Weiping Yuan,
Zhaojun Zhang,
Xiaofan Zhu,
Xiangdong Fang
Affiliations
Rudan Xiao
Beijing Institute of Genomics, Chinese Academy of Sciences & China National Center for Bioinformation, Beijing 100101, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China
Lijuan Zhang
Beijing Institute of Genomics, Chinese Academy of Sciences & China National Center for Bioinformation, Beijing 100101, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China
Zijuan Xin
Beijing Institute of Genomics, Chinese Academy of Sciences & China National Center for Bioinformation, Beijing 100101, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China
Junwei Zhu
Beijing Institute of Genomics, Chinese Academy of Sciences & China National Center for Bioinformation, Beijing 100101, P.R. China
Qian Zhang
Beijing Institute of Genomics, Chinese Academy of Sciences & China National Center for Bioinformation, Beijing 100101, P.R. China
Guangmin Zheng
Beijing Institute of Genomics, Chinese Academy of Sciences & China National Center for Bioinformation, Beijing 100101, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China
Siyun Chu
Beijing Institute of Genomics, Chinese Academy of Sciences & China National Center for Bioinformation, Beijing 100101, P.R. China
Jing Wu
Beijing Institute of Genomics, Chinese Academy of Sciences & China National Center for Bioinformation, Beijing 100101, P.R. China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, P.R. China
Lu Zhang
Beijing Institute of Genomics, Chinese Academy of Sciences & China National Center for Bioinformation, Beijing 100101, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China
Yang Wan
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
Xiaojuan Chen
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
Weiping Yuan
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
Zhaojun Zhang
Beijing Institute of Genomics, Chinese Academy of Sciences & China National Center for Bioinformation, Beijing 100101, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, P.R. China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, P.R. China; Beijing Key Laboratory of Genome and Precision Medicine Technologies, Beijing 100101, P.R. China; Corresponding author
Xiaofan Zhu
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Corresponding author
Xiangdong Fang
Beijing Institute of Genomics, Chinese Academy of Sciences & China National Center for Bioinformation, Beijing 100101, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, P.R. China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, P.R. China; Beijing Key Laboratory of Genome and Precision Medicine Technologies, Beijing 100101, P.R. China; Corresponding author
Summary: Energy metabolism in the context of erythropoiesis and related diseases remains largely unexplored. Here, we developed a primary cell model by differentiating hematopoietic stem progenitor cells toward the erythroid lineage and suppressing the mitochondrial oxidative phosphorylation (OXPHOS) pathway. OXPHOS suppression led to differentiation failure of erythroid progenitors and defects in ribosome biogenesis. Ran GTPase-activating protein 1 (RanGAP1) was identified as a target of mitochondrial OXPHOS for ribosomal defects during erythropoiesis. Overexpression of RanGAP1 largely alleviated erythroid defects resulting from OXPHOS suppression. Coenzyme Q10, an activator of OXPHOS, largely rescued erythroid defects and increased RanGAP1 expression. Patients with Diamond-Blackfan anemia (DBA) exhibited OXPHOS suppression and a concomitant suppression of ribosome biogenesis. RNA-seq analysis implied that the substantial mutation (approximately 10%) in OXPHOS genes accounts for OXPHOS suppression in these patients. Conclusively, OXPHOS disruption and the associated disruptive mitochondrial energy metabolism are linked to the pathogenesis of DBA.
