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

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• 作者：Silvia Ravera ; Daniele Vaccaro ; Paola Cuccarolo ; Marta Columbaro ; Cristina Capanni ; Martina Bartolucci ; Isabella Panfoli ; Aless ; ro Morelli ; Carlo Dufour ; Enrico Cappelli ; Paolo Degan
• 关键词：Fanconi anemia ; Mitochondria ; Respiration ; Reactive oxygen species ; ATP
• 刊名：Biochimie
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：95
• 期：10
• 页码：1828-1837
• 全文大小：1894 K

文摘

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.