Alternative metabolic pathways for energy supply and resistance to apoptosis in Fanconi anaemia.

Deregulation of control of the apoptotic process in Fanconi anaemia (FA) appears to be one of the main features of this disease at the cellular level. We show here that FA cells are resistant to treatments with rhodamine-1,2,3 and doxycycline, which both interfere with mitochondrial functionality by different mechanisms. In contrast, normal lymphoblastoid cells are severely affected by these treatments, which result in acute ATP depletion and a significant enhancement of the fraction of cells undergoing apoptotic cell death. FA cells are very sensitive to the action of 2-deoxy-D-glucose (2dG) and iodoacetic acid (IAA), two inhibitors of glycolytic metabolism. The ability of FA cells to sustain metabolic insults interfering with energy production and balance may be linked with the pathological manifestations of the disease, including susceptibility to acute myeloid leukemia. These findings suggest that FA genes may be involved in a pathway that mediates a protective response to stress. We suggest that a peculiar metabolic regulation in FA cells could explain both defective apoptosis and susceptibility to oxidative stress.