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

doi:10.1016/j.isci.2024.109172

Disruption of mitochondrial energy metabolism is a putative pathogenesis of Diamond-Blackfan anemia

iScience. 2024 Feb 9;27(3):109172. doi: 10.1016/j.isci.2024.109172. eCollection 2024 Mar 15.

Authors

Rudan Xiao^{1

2}, Lijuan Zhang^{1

2}, Zijuan Xin^{1

2}, Junwei Zhu¹, Qian Zhang¹, Guangmin Zheng^{1

2}, Siyun Chu¹, Jing Wu^{1

3}, Lu Zhang^{1

2}, Yang Wan⁴, Xiaojuan Chen⁴, Weiping Yuan⁴, Zhaojun Zhang^{1

2

3

5

6}, Xiaofan Zhu⁴, Xiangdong Fang^{1

2

3

5

6}

Affiliations

¹ Beijing Institute of Genomics, Chinese Academy of Sciences & China National Center for Bioinformation, Beijing 100101, P.R. China.
² University of Chinese Academy of Sciences, Beijing 100049, P.R. China.
³ Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, P.R. China.
⁴ 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.
⁵ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, P.R. China.
⁶ Beijing Key Laboratory of Genome and Precision Medicine Technologies, Beijing 100101, P.R. China.

Abstract

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.

Keywords: Cell biology; Cellular physiology; Developmental biology.