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

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.

SUBMITTER: Xiao R

PROVIDER: S-EPMC10897903 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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

Xiao Rudan R Zhang Lijuan L Xin Zijuan Z Zhu Junwei J Zhang Qian Q Zheng Guangmin G Chu Siyun S Wu Jing J Zhang Lu L Wan Yang Y Chen Xiaojuan X Yuan Weiping W Zhang Zhaojun Z Zhu Xiaofan X Fang Xiangdong X

iScience 20240209 3

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 O ...[more]

PMID: 38414864

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Project description:Diamond Blackfan Anemia (DBA) is a rare, congenital erythrocyte aplasia that is usually caused by haploinsufficiency of ribosomal proteins due to diverse mutations in one of several ribosomal protein genes. A striking feature of this disease is that a range of different mutations in ribosomal proteins results in similar disease phenotypes primarily characterized by erythrocyte abnormalities and macrocytic anemia, while most other cell types are minimally affected. Previously, we analyzed the erythrocyte membrane proteomes of several DBA patients and identified several proteins that are not typically associated with this cell type that suggested inflammatory mechanisms contribute to the pathogenesis of DBA. In this study, we evaluated the erythrocyte cytosolic proteome of DBA patients through in-depth analysis of hemoglobin-depleted erythrocyte cytosol. The simple, reproducible, hemoglobin depletion using nickel columns enabled in-depth analysis of over 1000 cytosolic erythrocyte proteins with minimal subsequent fractionation of the proteome. Label-free quantitation and statistical analysis identified 29 proteins that were significantly changed in DBA patients compared to matched healthy control donors. Some of the proteins that were significantly increased in DBA erythrocyte cytoplasm included three proteasome subunit beta proteins that make up the immunoproteasome and proteins induced by interferon-γ such as n-myc interactor and interferon-induced 25 kDa protein [NMI and IFI35 respectively]. Pathway analysis confirmed the presence of an inflammatory signature with erythrocytes of DBA patients and predicted key upstream regulators including mitogen activated kinase 1, interferon-γ, tumor suppressor p53, and tumor necrosis factor. These results show that erythrocytes in DBA patients are intrinsically different from those in healthy controls which may be due to an inflammatory response resulting from the inherent molecular defect of ribosomal protein haploinsufficiency or changes in the bone marrow microenvironment that leads to red cell aplasia in DBA patients.

Dataset Information

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

Publications

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

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