Dysregulated Ca2+ homeostasis in Fanconi anemia cells

Sci Rep. 2015 Jan 28;5:8088. doi: 10.1038/srep08088.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Antioxidants / pharmacology
  • Calcium / metabolism*
  • Calcium-Transporting ATPases / metabolism
  • Carbocyanines / metabolism
  • Cell Line
  • Fanconi Anemia / metabolism*
  • Fanconi Anemia / pathology*
  • Fanconi Anemia Complementation Group Proteins / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Heterocyclic Compounds, 3-Ring / metabolism
  • Homeostasis* / drug effects
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Kinetics
  • Microscopy, Confocal
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Models, Biological
  • Resveratrol
  • Stilbenes / pharmacology
  • Thapsigargin / pharmacology

Substances

  • Antioxidants
  • Carbocyanines
  • Fanconi Anemia Complementation Group Proteins
  • Heterocyclic Compounds, 3-Ring
  • Stilbenes
  • rhod-2
  • 3,3'-dihexyl-2,2'-oxacarbocyanine
  • Thapsigargin
  • Hydrogen Peroxide
  • Calcium-Transporting ATPases
  • Resveratrol
  • Calcium
  • Acetylcysteine