Why is an energy metabolic defect the common outcome in BMFS?

Abstract

Inherited bone marrow failure syndromes (BMFS) are rare, distressing, inherited blood disorders of children. Although the genetic origin of these pathologies involves genes with different functions, all are associated with progressive haematopoietic impairment and an excessive risk of malignancies. Defects in energy metabolism induce oxidative stress, impaired energy production and an unbalanced ratio between ATP and AMP. This assumes an important role in self-renewal and differentiation in haematopoietic stem cells (HSC) and can play an important role in bone marrow failure. Defects in energetic/respiratory metabolism, in particular in FA and SDS cells, have been described recently and seem to be a pertinent argument in the discussion of the haematopoietic defect in BMFS, as an alternative to the hypotheses already established on this subject, which may shed new light on the evolution of these diseases. KEYWORDSBone marrow failures, oxidative stress, energy metabolism, cancer prone diseases, hematopoietic stem cellsThe bone marrow failure syndromes (BMFS) include a group of disorders than can be either inherited or acquired, and share phenotypic hallmarks of age-related diseases. The aging process in particular affects haematopoietic stem cells, inducing reduced regenerative potential with a possible increase in genetically unstable cells and malignancy. Although the genetic origin of these pathologies involves genes with different functions 1,2 (e.g., DNA repair, ribosome biogenesis, and telomere maintenance) there is a common final pathway, yet still largely elusive, by which HSC are unable to support the production of blood cells. 3Telomere maintenance, DNA repair and oxidative stress are biochemically interrelated processes responsible for cellular aging. Even though the aging mechanism has not yet been clarified and several theories are proposed, 4 mitochondrial metabolism, reactive oxygen species (ROS) and cellular antioxidant systems maintain a central role in the aging process. 5,6 In fact, oxidative stress and ROS increment are a common factor in BMFS. 7Fanconi's Anaemia (FA), Shwachman-Diamond Syndrome (SDS), Dyskeratosis Congenital (DC) and the Diamond-Blackfan Syndrome (DBA) are the most frequent inherited BMFS disorders. FA cells show chromosomal instability, hypersensitivity to crosslinking agents and defects of DNA repair mechanisms. These characteristics seem strikingly linked to defects in the oxidative stress response. In fact, chromosomal aberrations in FA lymphocytes are positively related to oxygen tension and spontaneous chromosomal instability is reduced by superoxide dismutase and catalase activity. Recently, it has been shown that antioxidant (AO) molecules improve haematopoiesis and reduce spontaneous and induced chromosomal instability in FA. Moreover, oxidative stress is a critical factor in the pathogenesis of bone marrow failure and leukemia progression in FA cells. 8,9 SDS cells have a defect in ribosome biogenesis, chemotaxis, mitotic spindle formation and cellular stress...

Concentration‐dependent metabolic effects of metformin in healthy and Fanconi anemia lymphoblast cells

“…As mentioned above, MET has been tested in several diseases with the aim of reducing oxidative stress and improving the energetic/glucose metabolism (Hou et al, ; Khallaghi et al, ; Victor et al, ). Herein, we tested the effect of MET on Fanconi Anaemia because this pathology is characterized by an impairment of OXPHOS machinery due to a failed electron transport between complexes I and III (Cappelli et al, ; Degan et al, ; Ravera et al, ). Our attempt to use MET on FA cells shows that, although low concentrations of MET (15 and 150 μM) induce an increase in mitochondrial mass, the respiratory ability and the ATP/AMP ratio improve only poorly, as does the response to insulin stimuli and to oxidative stress.…”

“…Fanconi Anemia is a genetic bone marrow failure syndrome with a high disposition to leukemia and other cancers (de Winter & Joenje, ). Although the DNA repair defect has a primary role in cellular phenotype, FA cells also show a respiratory chain defect, which causes an energetic impairment and an increase in the oxidative stress production (Degan, Ravera, & Cappelli, ; Ravera et al, ). Moreover, the oxidative stress causes FA insulin resistance and glucose metabolism related disorders (Li et al, ), which are present in about the 50% of FA patients (Elder et al, ).…”

Fanconi anemia: from DNA repair to metabolism

“…In conclusion, we believe that the evaluation of the energy metabolism alterations could open new horizons for FA patients diagnosis and therapy. This can also hold true for other bone marrow failure diseases, which share with FA some common features [10].…”