Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity

Abstract

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.

A new perspective on oxidation of DNA repair proteins and cancer

“…Thus, the Cys and truncation mutants can be activated by DNA damage but not by oxidative stress [66,73]. These findings led to the conclusions that ATM acts to sense oxidative stress in cells and this may be important for a novel function of ATM, which is independent of DNA damage [66,74,75,107]. The ability of ATM to respond to oxidative stress by forming disulfide bonds may activate an alternate cellular response pathway that is necessary to prevent DNA damage by oxidative stress.…”

Autophagy and Redox Homeostasis in Parkinson’s: A Crucial Balancing Act

“…Here, it phosphorylates PEX5 triggering ubiquitylation via the E3-like ubiquitin ligase complex, PEX2-PEX10-PEX12, and later recognition by cargo receptors [ 271 , 272 ]. H 2 O 2 treatment induces nuclear ATM redox disulfide bond formation, indirectly promoting the downstream expression of proteins involved in the pentose phosphate pathway, and an activator effect via nytrosilation has also been suggested [ 273 – 275 ].…”

A prospect of cell immortalization combined with matrix microenvironmental optimization strategy for tissue engineering and regeneration

“…For stress-induced senescence, TGFβ contributes to ROS production and activation of DDR during the senescence of human fibroblasts and bone marrow-derived MSCs (BMSCs) [64, 65]. The kinase ataxia-telangiectasia mutated (ATM) is a key player in nuclear DDR [66]. Meanwhile, TGFβ is required for oncogene-induced senescence that is independent of the p16/Rb and p53 pathways; attenuation of TGFβ inhibits premature senescence in human mammary epithelial cells [67, 68].…”