A new frontier in Fanconi anemia: From DNA repair to ribosome biogenesis

Gueiderikh, Anna; Maczkowiak-Chartois, Frédérique; Rosselli, Filippo

doi:10.1016/j.blre.2021.100904

Cited by 26 publications

(9 citation statements)

References 227 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The direct correlation between RS, mitochondrial metabolism and mitophagy is difficult to explain. Our data indicate that mTOR signaling and mTOR-related lysosomal biogenesis may sense RS and increase overall metabolic activity including c-Myc ( 23 ) and ribosome biogenesis ( 24 ), though further investigation is needed. In conclusion, this manuscript provides evidence for the involvement of RS in the metabolic regulation of HSCs by FANCD2 deficiency and highlights the unique characteristics of the FL HSCs compared to adult BM HSCs.…”

Section: Discussionmentioning

confidence: 92%

Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells

Mochizuki-Kashio

Otsuki²,

Fujiki³

et al. 2023

Front. Oncol.

View full text Add to dashboard Cite

Fanconi Anemia (FA) is an inherited bone marrow (BM) failure disorder commonly diagnosed during school age. However, in murine models, disrupted function of FA genes leads to a much earlier decline in fetal liver hematopoietic stem cell (FL HSC) number that is associated with increased replication stress (RS). Recent reports have shown mitochondrial metabolism and clearance are essential for long-term BM HSC function. Intriguingly, impaired mitophagy has been reported in FA cells. We hypothesized that RS in FL HSC impacts mitochondrial metabolism to investigate fetal FA pathophysiology. Results show that experimentally induced RS in adult murine BM HSCs evoked a significant increase in mitochondrial metabolism and mitophagy. Reflecting the physiological RS during development in FA, increase mitochondria metabolism and mitophagy were observed in FANCD2-deficient FL HSCs, whereas BM HSCs from adult FANCD2-deficient mice exhibited a significant decrease in mitophagy. These data suggest that RS activates mitochondrial metabolism and mitophagy in HSC.

show abstract

Section: Discussionmentioning

confidence: 92%

Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells

Mochizuki-Kashio

Otsuki²,

Fujiki³

et al. 2023

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…Mutation of FANC genes is the underlying etiology in Fanconi anemia, a rare disorder characterized by genomic instability, bone marrow hypocellularity, and subsequent pancytopenia of the three blood cell lineages. 57 The increased transcription of genes encoding heat shock proteins suggest that Plasmodium infection of late erythroblasts may produce genotoxic or proteotoxic effects that result in dyserythropoiesis. Although further experiments are needed to evaluate the extent of damage to the cell during infection, increased transcription suggests a cell intrinsic host response aimed at protecting developing erythroblasts from detrimental effects of infection.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparuminfection of human erythroblasts induces transcriptional changes associated with dyserythropoiesis

Feldman

Ryan

Egan

2023

Preprint

View full text Add to dashboard Cite

During development down the erythroid lineage, hematopoietic stem cells undergo dramatic changes to cellular morphology and function in response to a complex and tightly regulated program of gene expression. In malaria infection,Plasmodium spp.parasites accumulate in the bone marrow parenchyma, and emerging evidence suggests erythroblastic islands are a protective site for parasite development into gametocytes. While it has been observed thatPlasmodium falciparuminfection of late-stage erythroblasts can delay terminal erythroid differentiation and enucleation, the mechanism(s) underlying this phenomenon are unknown. Here, we apply RNA-seq after fluorescence-activated cell sorting (FACS) of infected erythroblasts to identify transcriptional responses to direct and indirect interaction withPlasmodium falciparum. Four developmental stages of erythroid cells were analyzed: proerythroblast, basophilic erythroblast, polychromatic erythroblast, and orthochromatic erythroblast. We found extensive transcriptional changes in infected erythroblasts compared to uninfected cells in the same culture, including dysregulation of genes involved in erythroid proliferation and developmental processes. Whereas some indicators of cellular oxidative and proteotoxic stress were common across all stages of erythropoiesis, many responses were specific to cellular processes associated with developmental stage. Together, our results evidence multiple possible avenues by which parasite infection can induce dyserythropoiesis at specific points along the erythroid continuum, advancing our understanding of the molecular determinants of malaria anemia.

show abstract

“…Fanconi anemia (FA) is a rare genetic disorder, recessive autosomal or X-linked [ 1 ]. FA phenotype can be very heterogeneous, with clinical manifestations ranging from congenital malformations to metabolic dysfunction susceptibility and increased risk of cancer developing, particularly leukemia and squamous cell carcinoma [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Altered Mitochondrial Dynamic in Lymphoblasts and Fibroblasts Mutated for FANCA-A Gene: The Central Role of DRP1

Bertola

Bruno

Capanni

et al. 2023

IJMS

View full text Add to dashboard Cite

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure and aplastic anemia. So far, 23 genes are involved in this pathology, and their mutations lead to a defect in DNA repair. In recent years, it has been observed that FA cells also display mitochondrial metabolism defects, causing an accumulation of intracellular lipids and oxidative damage. However, the molecular mechanisms involved in the metabolic alterations have not yet been elucidated. In this work, by using lymphoblasts and fibroblasts mutated for the FANC-A gene, oxidative phosphorylation (OxPhos) and mitochondria dynamics markers expression was analyzed. Results show that the metabolic defect does not depend on an altered expression of the proteins involved in OxPhos. However, FA cells are characterized by increased uncoupling protein UCP2 expression. FANC-A mutation is also associated with DRP1 overexpression that causes an imbalance in the mitochondrial dynamic toward fission and lower expression of Parkin and Beclin1. Treatment with P110, a specific inhibitor of DRP1, shows a partial mitochondrial function recovery and the decrement of DRP1 and UCP2 expression, suggesting a pivotal role of the mitochondrial dynamics in the etiopathology of Fanconi anemia.

show abstract

A new frontier in Fanconi anemia: From DNA repair to ribosome biogenesis

Cited by 26 publications

References 227 publications

Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells

Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells

Plasmodium falciparuminfection of human erythroblasts induces transcriptional changes associated with dyserythropoiesis

Altered Mitochondrial Dynamic in Lymphoblasts and Fibroblasts Mutated for FANCA-A Gene: The Central Role of DRP1

Contact Info

Product

Resources

About