Disruption of Mitochondrial Energy Metabolism is a Putative Pathogenesis of Diamond-Blackfan Anemia

Overview

Journal iScience

Publisher Cell Press

Date 2024 Feb 28

PMID 38414864

Authors

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

Soon will be listed here.

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.

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