Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity

Abstract

<p class="first" id="P1">Mitochondria are integral to cellular energy metabolism and ATP production, and are involved in regulating many cellular processes. Mitochondria produce reactive oxygen species (ROS) that can damage cellular components but that 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 by its ROS-dependent formation of disulfide-linked dimers. Here, we found that mitochondria-derived hydrogen peroxide promoted ATM redox 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 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 expression 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. </p>