Changes in vimentin, lamin A/C and mitofilin induce aberrant cell organization in fibroblasts from Fanconi anemia complementation group A (FA-A) patients

Capanni, Cristina; Bruschi, Maurizio; Columbaro, Marta; Cuccarolo, Paola; Ravera, Silvia; Dufour, Carlo; Candiano, Giovanni; Petretto, Andrea; Degan, Paolo; Cappelli, Enrico

doi:10.1016/j.biochi.2013.06.024

Cited by 17 publications

(29 citation statements)

References 44 publications

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“…MR fragmentation reduce the interaction from the two reticula lowering Ca 2+ passage and inhibiting membrane depolarization that results in resistance to apoptosis. In FA cells treated with hydrogen peroxide we observed [1,53] MR fragmentation and low membrane depolarization suggesting an adaptive cell organization [68,69] .…”

Section: Camentioning

confidence: 76%

“…This deficiency might be associated with an intrinsic functional defect in FA mitochondria. Interestingly enough, mitochondria appear to play a role as cell-fate determinants in the asymmetry HSC self-renewal process [65] and we contributed to thoroughly describe the mitochondrial functional defect in FA [53,54,55,66] . On the other hand, it was shown that intra-mitochondrial Ca 2+ can control oxidative phosphorylation, i.e., indirectly, the ROS production.…”

Section: Camentioning

confidence: 99%

“…Concerning FA we recently contribute to describe several defects associated with structural elements (lamin and mitofilin), metallo-proteinases, morphological and functional elements (mitochondria and nuclei) [53,54,55,56] . These defects were essentially viewed in the single perspective of a red-ox unbalance, as treatment with selected antioxidants generally restored physiological conditions.…”

Section: Implication Of An Altered Calcium Homeostasis In Famentioning

confidence: 99%

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Altered Calcium and Red-ox homeostasis underline defective haematopoiesis in Fanconi Anemia

2015

Sci Proc

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Section: Camentioning

confidence: 76%

Section: Camentioning

confidence: 99%

Section: Implication Of An Altered Calcium Homeostasis In Famentioning

confidence: 99%

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Altered Calcium and Red-ox homeostasis underline defective haematopoiesis in Fanconi Anemia

2015

Sci Proc

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“…Another change that somatic cells must undergo during reprogramming is altered cell structure, including a mesenchymal-to-epithelial transition (if the starting cells are mesenchymal) and increased nuclear-to-cytoplasmic ratio. In this regard, FA has been shown to affect the structure of cultured cells through deregulation of cytoskeletal proteins, including the mesenchymal protein vimentin, and may thus inhibit reprogramming through the deregulation of cell structure and organization (50). Finally, activated FANCD2 has recently been shown to function as a transcription factor that can suppress oncogene expression (51).…”

Section: Discussionmentioning

confidence: 99%

High-Risk Human Papillomavirus E6 Protein Promotes Reprogramming of Fanconi Anemia Patient Cells through Repression of p53 but Does Not Allow for Sustained Growth of Induced Pluripotent Stem Cells

Chlon

Hoskins

Mayhew

et al. 2014

J Virol

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DNA repair plays a crucial role in embryonic and somatic stem cell biology and cell reprogramming. The Fanconi anemia (FA) pathway, which promotes error-free repair of DNA double-strand breaks, is required for somatic cell reprogramming to induced pluripotent stem cells (iPSC). Thus, cells from Fanconi anemia patients, which lack this critical pathway, fail to be reprogrammed to iPSC under standard conditions unless the defective FA gene is complemented. In this study, we utilized the oncogenes of high-risk human papillomavirus 16 (HPV16) to overcome the resistance of FA patient cells to reprogramming. We found that E6, but not E7, recovers FA iPSC colony formation and, furthermore, that p53 inhibition is necessary and sufficient for this activity. The iPSC colonies resulting from each of these approaches stained positive for alkaline phosphatase, NANOG, and Tra-1-60, indicating that they were fully reprogrammed into pluripotent cells. However, FA iPSC were incapable of outgrowth into stable iPSC lines regardless of p53 suppression, whereas their FA-complemented counterparts grew efficiently. Thus, we conclude that the FA pathway is required for the growth of iPSC beyond reprogramming and that p53-independent mechanisms are involved. IMPORTANCEA novel approach is described whereby HPV oncogenes are used as tools to uncover DNA repair-related molecular mechanisms affecting somatic cell reprogramming. The findings indicate that p53-dependent mechanisms block FA cells from reprogramming but also uncover a previously unrecognized defect in FA iPSC proliferation independent of p53.

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“…In FA lymphocytes, mitochondria are swollen with matrix rarefaction and altered cristae, while in primary fibroblasts, fragmentation of the mitochondrial reticulum has been described. 16,23 Moreover, altered mitochondrial structures are also present in cell models of DBA, while human SDS lymphocytes show normal mitochondrial structure when observed under electron microscopy. 17,19 Moreover, the energetic function of mitochondria depends on different factors, including several signaling pathways.…”

mentioning

confidence: 98%

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

2016

Self Cite

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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...

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Changes in vimentin, lamin A/C and mitofilin induce aberrant cell organization in fibroblasts from Fanconi anemia complementation group A (FA-A) patients

Cited by 17 publications

References 44 publications

Altered Calcium and Red-ox homeostasis underline defective haematopoiesis in Fanconi Anemia

Altered Calcium and Red-ox homeostasis underline defective haematopoiesis in Fanconi Anemia

High-Risk Human Papillomavirus E6 Protein Promotes Reprogramming of Fanconi Anemia Patient Cells through Repression of p53 but Does Not Allow for Sustained Growth of Induced Pluripotent Stem Cells

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

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