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Sci Signal. 2018 Jul 10;11(538). pii: eaaq0702. doi: 10.1126/scisignal.aaq0702.

Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity.

Author information

1
Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA.
2
Howard Hughes Medical Institute, Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
3
Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, USA.
4
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02155, USA.
5
Department of Chemistry, Appalachian State University, Boone, NC 28608, USA.
6
Department of Chemistry, Appalachian State University, Boone, NC 28608, USA. gshadel@salk.edu christianbe@appstate.edu.
7
Salk Institute for Biological Studies, La Jolla, CA 92037, USA. gshadel@salk.edu christianbe@appstate.edu.

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.

PMID:
29991649
PMCID:
PMC6042875
DOI:
10.1126/scisignal.aaq0702
[Indexed for MEDLINE]
Free PMC Article

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