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ATM is activated by ATP depletion and modulates mitochondrial function through NRF1
Hei-Man Chow1,2, Aifang Cheng3, Xuan Song3
1Division of Life Science and The State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong heimanchow@ust.hk.
The Journal of Cell Biology
|January 16, 2019
Summary
Ataxia-telangiectasia (A-T) involves ATM gene mutations. This study reveals ATM protects mitochondria by boosting ATP production via NRF1, crucial for neuronal survival.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Ataxia-telangiectasia (A-T) is an autosomal recessive disorder linked to ATM gene mutations.
- It causes cerebellar Purkinje cell loss, impacting high-energy-demand neurons.
Purpose of the Study:
- To investigate the role of ATM in cellular energy homeostasis and mitochondrial function.
- To understand how ATM activation by oxidative stress impacts neuronal survival in A-T.
Main Methods:
- Investigated ATP depletion-induced reactive oxygen species (ROS) generation and ATM activation.
- Analyzed ATM-mediated phosphorylation of NRF1 and its downstream effects on mitochondrial gene expression.
- Examined cellular ATP replenishment and survival in ATM-deficient cells.
Main Results:
- ATP depletion generates ROS, activating ATM.
- ATM activation by oxidative stress (not DNA damage) phosphorylates NRF1, promoting mitochondrial gene upregulation and enhancing electron transport chain (ETC) capacity.
- ATM-deficient cells show impaired ATP replenishment and are vulnerable to chronic ATP insufficiency.
Conclusions:
- ATM acts as a guardian of mitochondrial output and genomic integrity.
- In A-T, impaired ATM function hinders Purkinje cells' response to energy demands, contributing to neurodegeneration.
- Alternative fuel sources may offer therapeutic potential for A-T symptoms.
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