Journal
MOLECULAR AND CELLULAR BIOCHEMISTRY
Volume 476, Issue 1, Pages 417-423Publisher
SPRINGER
DOI: 10.1007/s11010-020-03917-1
Keywords
ATM kinase; Leukemia; Lymphoma; Mitophagy; ROS
Categories
Funding
- CLL Global Research Foundation
- NIH/NCI through MD Anderson's Cancer Center Support Grant [CA016672]
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ATM, a critical DNA damage sensor, is frequently altered in several human cancers and its loss is associated with defective mitochondrial autophagy. Ionophore-induced mitophagy triggers oxidative stress-induced ATM phosphorylation through ROS activation, suggesting that while ATM kinase does not participate in mitophagy, it is activated via elevated ROS.
Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor, also possesses non-nuclear functions owing to its presence in extra-nuclear compartments, including peroxisomes, lysosomes, and mitochondria. ATM is frequently altered in several human cancers. Recently, we and others have shown that loss of ATM is associated with defective mitochondrial autophagy (mitophagy) in ataxia-telangiectasia (A-T) fibroblasts and B-cell lymphomas. Further, we reported that ATM protein but not ATM kinase activity is required for mitophagy. However, the mechanism of ATM kinase activation during ionophore-induced mitophagy is unknown. In the work reported here, using several ionophores in A-T and multiple T-cell and B-cell lymphoma cell lines, we show that ionophore-induced mitophagy triggers oxidative stress-induced ATM(Ser1981)phosphorylation through ROS activation, which is different from neocarzinostatin-induced activation of ATM(Ser1981), Smc1(Ser966), and Kap1(Ser824). We used A-T cells overexpressed with WT or S1981A (auto-phosphorylation dead) ATM plasmids and show that ATM is activated by ROS-induced oxidative stress emanating from ionophore-induced mitochondrial damage and mitophagy. The antioxidantsN-acetylcysteine and glutathione significantly inhibited ROS production and ATM(Ser1981)phosphorylation but failed to inhibit mitophagy as determined by retroviral infection with mt-mKeima construct followed by lysosomal dual-excitation ratiometric pH measurements. Our data suggest that while ATM kinase does not participate in mitophagy, it is activated via elevated ROS.
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