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Dysregulated Ca2+ homeostasis in Fanconi anemia cells.

Usai C, Ravera S, Cuccarolo P, Panfoli I, Dufour C, Cappelli E, Degan P - Sci Rep (2015)

Bottom Line: Many alterations in FA physiology appear linked to red-ox unbalance including alterations in the morphology and structure of nuclei, intermediate filaments and mitochondria, defective respiration, reduced ATP production and altered ATP/AMP ratio.These defects are consistently associated with impaired oxygen metabolism indeed treatment with antioxidants N-acetylcysteine (NAC) and resveratrol (RV) does rescue FA physiology.The defects associated with the altered Ca(2+) homeostasis appear consistently overlapping those related to the unbalanced oxidative metabolism in FA cells underlining a contiguity between oxidative stress and calcium homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biophysics, National Research Council, 16149 Genova, Italy.

ABSTRACT
Fanconi Anemia (FA) is a rare and complex inherited blood disorder associated with bone marrow failure and malignancies. Many alterations in FA physiology appear linked to red-ox unbalance including alterations in the morphology and structure of nuclei, intermediate filaments and mitochondria, defective respiration, reduced ATP production and altered ATP/AMP ratio. These defects are consistently associated with impaired oxygen metabolism indeed treatment with antioxidants N-acetylcysteine (NAC) and resveratrol (RV) does rescue FA physiology. Due to the importance of the intracellular calcium signaling and its key function in the control of intracellular functions we were interested to study calcium homeostasis in FA. We found that FANCA cells display a dramatically low intracellular calcium concentration ([Ca(2+)]i) in resting conditions. This condition affects cellular responses to stress. The flux of Ca(2+) mobilized by H2O2 from internal stores is significantly lower in FANCA cells in comparison to controls. The low basal [Ca(2+)]i in FANCA appears to be an actively maintained process controlled by a finely tuned interplay between different intracellular Ca(2+) stores. The defects associated with the altered Ca(2+) homeostasis appear consistently overlapping those related to the unbalanced oxidative metabolism in FA cells underlining a contiguity between oxidative stress and calcium homeostasis.

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Related in: MedlinePlus

Schematic representation of the functions and relationships that appear affected by the abnormal [Ca2+] and Red-Ox signaling in FANCA cells.Functions directly affected by the altered calcium signaling are indicated by the red double arrows. Following alteration of these primary targets other internal relationships, indicated by the dark red arrows, may result modified.
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f4: Schematic representation of the functions and relationships that appear affected by the abnormal [Ca2+] and Red-Ox signaling in FANCA cells.Functions directly affected by the altered calcium signaling are indicated by the red double arrows. Following alteration of these primary targets other internal relationships, indicated by the dark red arrows, may result modified.

Mentions: In conclusion it appears that the defects attributed to altered Ca2+ homeostasis are consistently overlapping those related to alterations of the oxidative metabolism in FA cells. Indeed the abnormal manipulation of these signals results in diffuse defects which affects FA cells phenotype as a whole (Fig. 4). The peculiar Ca2+ signaling represents a distinctive trait that may be of value in the perspective of the knowledge of the biochemical mechanisms of FA with the final aim of possible therapeutic intervention.


Dysregulated Ca2+ homeostasis in Fanconi anemia cells.

Usai C, Ravera S, Cuccarolo P, Panfoli I, Dufour C, Cappelli E, Degan P - Sci Rep (2015)

Schematic representation of the functions and relationships that appear affected by the abnormal [Ca2+] and Red-Ox signaling in FANCA cells.Functions directly affected by the altered calcium signaling are indicated by the red double arrows. Following alteration of these primary targets other internal relationships, indicated by the dark red arrows, may result modified.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4308711&req=5

f4: Schematic representation of the functions and relationships that appear affected by the abnormal [Ca2+] and Red-Ox signaling in FANCA cells.Functions directly affected by the altered calcium signaling are indicated by the red double arrows. Following alteration of these primary targets other internal relationships, indicated by the dark red arrows, may result modified.
Mentions: In conclusion it appears that the defects attributed to altered Ca2+ homeostasis are consistently overlapping those related to alterations of the oxidative metabolism in FA cells. Indeed the abnormal manipulation of these signals results in diffuse defects which affects FA cells phenotype as a whole (Fig. 4). The peculiar Ca2+ signaling represents a distinctive trait that may be of value in the perspective of the knowledge of the biochemical mechanisms of FA with the final aim of possible therapeutic intervention.

Bottom Line: Many alterations in FA physiology appear linked to red-ox unbalance including alterations in the morphology and structure of nuclei, intermediate filaments and mitochondria, defective respiration, reduced ATP production and altered ATP/AMP ratio.These defects are consistently associated with impaired oxygen metabolism indeed treatment with antioxidants N-acetylcysteine (NAC) and resveratrol (RV) does rescue FA physiology.The defects associated with the altered Ca(2+) homeostasis appear consistently overlapping those related to the unbalanced oxidative metabolism in FA cells underlining a contiguity between oxidative stress and calcium homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biophysics, National Research Council, 16149 Genova, Italy.

ABSTRACT
Fanconi Anemia (FA) is a rare and complex inherited blood disorder associated with bone marrow failure and malignancies. Many alterations in FA physiology appear linked to red-ox unbalance including alterations in the morphology and structure of nuclei, intermediate filaments and mitochondria, defective respiration, reduced ATP production and altered ATP/AMP ratio. These defects are consistently associated with impaired oxygen metabolism indeed treatment with antioxidants N-acetylcysteine (NAC) and resveratrol (RV) does rescue FA physiology. Due to the importance of the intracellular calcium signaling and its key function in the control of intracellular functions we were interested to study calcium homeostasis in FA. We found that FANCA cells display a dramatically low intracellular calcium concentration ([Ca(2+)]i) in resting conditions. This condition affects cellular responses to stress. The flux of Ca(2+) mobilized by H2O2 from internal stores is significantly lower in FANCA cells in comparison to controls. The low basal [Ca(2+)]i in FANCA appears to be an actively maintained process controlled by a finely tuned interplay between different intracellular Ca(2+) stores. The defects associated with the altered Ca(2+) homeostasis appear consistently overlapping those related to the unbalanced oxidative metabolism in FA cells underlining a contiguity between oxidative stress and calcium homeostasis.

Show MeSH
Related in: MedlinePlus