Affiliation:
1. Division of Life Science and The State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong
2. Institute for Advanced Study, Hong Kong University of Science and Technology, Hong Kong
3. Department of Cell Biology and Neuroscience, Rutgers University, New Brunswick, NJ
Abstract
Ataxia-telangiectasia (A-T) is an autosomal recessive disease caused by mutation of the ATM gene and is characterized by loss of cerebellar Purkinje cells, neurons with high physiological activity and dynamic ATP demands. Here, we show that depletion of ATP generates reactive oxygen species that activate ATM. We find that when ATM is activated by oxidative stress, but not by DNA damage, ATM phosphorylates NRF1. This leads to NRF1 dimerization, nuclear translocation, and the up-regulation of nuclear-encoded mitochondrial genes, thus enhancing the capacity of the electron transport chain (ETC) and restoring mitochondrial function. In cells lacking ATM, cells replenish ATP poorly following surges in energy demand, and chronic ATP insufficiency endangers cell survival. We propose that in the absence of ATM, cerebellar Purkinje cells cannot respond adequately to the increase in energy demands of neuronal activity. Our findings identify ATM as a guardian of mitochondrial output, as well as genomic integrity, and suggest that alternative fuel sources may ameliorate A-T disease symptoms.
Funder
Research Grants Council
RGC
HKUST
Alzheimer’s Association
National Institutes of Health
Publisher
Rockefeller University Press
Cited by
50 articles.
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