Mitochondrial respiratory chain Complex I defects in Fanconi anemia complementation group A

Biochimie. 2013 Oct;95(10):1828-37. doi: 10.1016/j.biochi.2013.06.006. Epub 2013 Jun 19.


Fanconi anemia (FA) is a rare and complex inherited blood disorder of the child. At least 15 genes are associated with the disease. The highest frequency of mutations belongs to groups A, C and G. Genetic instability and cytokine hypersensitivity support the selection of leukemic over non-leukemic stem cells. FA cellular phenotype is characterized by alterations in red-ox state, mitochondrial functionality and energy metabolism as reported in the past however a clear picture of the altered biochemical phenotype in FA is still elusive and the final biochemical defect(s) still unknown. Here we report an analysis of the respiratory fluxes in FANCA primary fibroblasts, lymphocytes and lymphoblasts. FANCA mutants show defective respiration through Complex I, diminished ATP production and metabolic sufferance with an increased AMP/ATP ratio. Respiration in FANCC mutants is normal. Treatment with N-acetyl-cysteine (NAC) restores oxygen consumption to normal level. Defective respiration in FANCA mutants appear correlated with the FA pro-oxidative phenotype which is consistent with the altered morphology of FANCA mitochondria. Electron microscopy measures indeed show profound alterations in mitochondrial ultrastructure and shape.

Keywords: ATP; Fanconi anemia; Mitochondria; Reactive oxygen species; Respiration.

MeSH terms

  • Acetylcysteine / pharmacology
  • Adenosine Monophosphate / metabolism
  • Adenosine Triphosphate / metabolism*
  • Adenylate Kinase / metabolism
  • Adolescent
  • Case-Control Studies
  • Cell Respiration / drug effects
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism*
  • Fanconi Anemia / genetics
  • Fanconi Anemia / metabolism*
  • Fanconi Anemia / pathology
  • Fanconi Anemia Complementation Group A Protein / genetics
  • Fanconi Anemia Complementation Group A Protein / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Humans
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism*
  • Lymphocytes / pathology
  • Microscopy, Electron
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mutation
  • Oxidation-Reduction
  • Oxygen Consumption / drug effects
  • Reactive Oxygen Species / metabolism


  • Fanconi Anemia Complementation Group A Protein
  • Reactive Oxygen Species
  • Adenosine Monophosphate
  • Adenosine Triphosphate
  • Adenylate Kinase
  • Electron Transport Complex I
  • Acetylcysteine