ATM is activated by ATP depletion and modulates mitochondrial function through NRF1 (ATM regulates ATP levels through NRF1)

A newly uncovered role for ATM protein deepens our understanding of the neurological symptoms of Ataxia-telangiectasia (A-T). With high energy demands, neurons of the brain, particularly Purkinje cells, require dynamic maintenance of ATP levels. ATM is the gene mutated in A-T and its deficiency compromises the activity of both the TCA cycle and the electron transport chain (ETC). We show that ATP insufficiency activates ATM via reactive oxygen species. While resting ATP levels are normal, Atm-/- cells have a reduced capacity to respond to surges in energy demands. This blunted response results from impaired ATM-mediated activation of nuclear respiratory factor-1 (NRF1). ATM phosphorylation of NRF1 at T259 dimerizes, translocates to the nucleus and drives mitochondrial gene expression, allowing increased mitochondrial protein synthesis. Our findings thus identify ATM not only as a guardian of genomic integrity bu also of mitochondrial output, suggesting that alternate fuel sources may ameliorate or delay ataxic symptoms in A-T.