Xiao Rudan, Zhang Lijuan, Xin Zijuan, Zhu Junwei, Zhang Qian, Zheng Guangmin, Chu Siyun, Wu Jing, Zhang Lu, Wan Yang, Chen Xiaojuan, Yuan Weiping, Zhang Zhaojun, Zhu Xiaofan, Fang Xiangdong
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.
iScience. 2024 Feb 9;27(3):109172. doi: 10.1016/j.isci.2024.109172. eCollection 2024 Mar 15.
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.
在红细胞生成及相关疾病背景下的能量代谢在很大程度上仍未被探索。在此，我们通过将造血干祖细胞向红系谱系分化并抑制线粒体氧化磷酸化（OXPHOS）途径，建立了一个原代细胞模型。OXPHOS抑制导致红系祖细胞分化失败及核糖体生物发生缺陷。Ran鸟苷三磷酸酶激活蛋白1（RanGAP1）被确定为红细胞生成过程中核糖体缺陷的线粒体OXPHOS靶点。RanGAP1的过表达在很大程度上减轻了OXPHOS抑制导致的红系缺陷。氧化磷酸化激活剂辅酶Q10在很大程度上挽救了红系缺陷并增加了RanGAP1的表达。先天性纯红细胞再生障碍性贫血（DBA）患者表现出OXPHOS抑制以及核糖体生物发生的伴随抑制。RNA测序分析表明，OXPHOS基因中的大量突变（约10%）导致了这些患者的OXPHOS抑制。总之，OXPHOS破坏及相关的线粒体能量代谢紊乱与DBA的发病机制有关。
