PMID: 30642892 RLIMS-P 1 Check other iTextMine results Issue Report
Title
| 1. | ATM is activated by ATP depletion and modulates mitochondrial function through NRF1. |
Abstract
| 2. | 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. |
| 3. | Here, we show that depletion of ATP generates reactive oxygen species that activate ATM. |
| 4. | We find that when ATM is activated by oxidative stress, but not by DNA damage, ATM phosphorylates NRF1. |
| 5. | 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. |
| 6. | In cells lacking ATM, cells replenish ATP poorly following surges in energy demand, and chronic ATP insufficiency endangers cell survival. |
| 7. | We propose that in the absence of ATM, cerebellar Purkinje cells cannot respond adequately to the increase in energy demands of neuronal activity. |
| 8. | 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. |
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Legend: SUBSTRATE KINASE INTERACTANT SITE GENE MIRNA ANOMALY EXPRESSION DISEASE OUTCOME/RESPONSE SR_DRUG DRUG CELL TRIGGER Normalized
Tool: RLIMS-P
| PTM enzyme | Substrate | Site | Sentence |
|---|---|---|---|
| ATM | NRF1 | 4 |