Research ArticleCELL STRESS

Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity

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Science Signaling  10 Jul 2018:
Vol. 11, Issue 538, eaaq0702
DOI: 10.1126/scisignal.aaq0702

Antioxidant role of ATM

The kinase ATM is integral to repairing damaged DNA. Hence, its loss has severe consequences for the development of disease. However, ATM also separately functions in the response to reactive oxygen species (ROS). ROS cause oxidative stress, a classic feature of cells in patients with the neurodegenerative disease ataxia telangiectasia (A-T), for which ATM was named. Using a mutant that impairs only the ROS-responsive function of ATM, Zhang et al. found that ROS produced by the mitochondria trigger the dimerization of ATM, which indirectly increased the expression and activity of an enzyme that shifts glucose flux from glycolysis and lactic acid production to the pentose phosphate pathway (PPP) and NADPH production, thereby increasing the antioxidant capacity of cells. These findings show how loss of the ROS-sensing, antioxidant function of ATM may contribute to the phenotypes of A-T.


Mitochondria are integral to cellular energy metabolism and ATP production and are involved in regulating many cellular processes. Mitochondria produce reactive oxygen species (ROS), which not only can damage cellular components but also participate in signal transduction. The kinase ATM, which is mutated in the neurodegenerative, autosomal recessive disease ataxia-telangiectasia (A-T), is a key player in the nuclear DNA damage response. However, ATM also performs a redox-sensing function mediated through formation of ROS-dependent disulfide-linked dimers. We found that mitochondria-derived hydrogen peroxide promoted ATM dimerization. In HeLa cells, ATM dimers were localized to the nucleus and inhibited by the redox regulatory protein thioredoxin 1 (TRX1), suggesting the existence of a ROS-mediated, stress-signaling relay from mitochondria to the nucleus. ATM dimer formation did not affect its association with chromatin in the absence or presence of nuclear DNA damage, consistent with the separation of its redox and DNA damage signaling functions. Comparative analysis of U2OS cells expressing either wild-type ATM or the redox sensing–deficient C2991L mutant revealed that one function of ATM redox sensing is to promote glucose flux through the pentose phosphate pathway (PPP) by increasing the abundance and activity of glucose-6-phosphate dehydrogenase (G6PD), thereby increasing cellular antioxidant capacity. The PPP produces the coenzyme NADPH needed for a robust antioxidant response, including the regeneration of TRX1, indicating the existence of a regulatory feedback loop involving ATM and TRX1. We propose that loss of the mitochondrial ROS-sensing function of ATM may cause cellular ROS accumulation and oxidative stress in A-T.

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