Oxidative phosphorylation pathway disruption is an alternative pathological mechanism leading to Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is a rare congenital disorder characterized by the failure of erythroid progenitor differentiation; however, the molecular mechanisms leading to erythroid defects remain unclear. By analyzing the transcriptomic profiles of bone marrow from patients with DBA (n = 10), we identified the oxidative phosphorylation (OXPHOS) pathway as a possible cause of DBA. We established a DBA cell model using differentiating hematopoietic stem progenitor cells in which the OXPHOS pathway had been suppressed to completely recapitulate the defects of erythroid progenitor differentiation, ribosome biogenesis, and heme biosynthesis, which are representative characteristics of patients with DBA. Disruption of the OXPHOS pathway led to ribosomal defects and associated erythroid defects via the abolishment of RanGAP1, which is pivotal in the RNA transport pathway. The established DBA cells exhibited an overall reduction in ribosomal proteins, but not the composition of ribosomal proteins in the ribosome, which altered the translation of a subset of transcripts specific for erythropoiesis. We revealed that the OXPHOS pathway participates in erythropoiesis, particularly at an early stage, and the relationship between the OXPHOS pathway and erythropoiesis was reinforced. CoQ10, an activator of OXPHOS, largely rescued the erythroid defects in DBA cells. Our results reveal that OXPHOS repression is an alternative pathological mechanism leading to DBA, demonstrating its potential as a therapeutic pathway in DBA. ### Competing Interest Statement The authors have declared no competing interest.