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Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress
Author(s) -
Cirotti Claudia,
Rizza Salvatore,
Giglio Paola,
Poerio Noemi,
Allega Maria Francesca,
Claps Giuseppina,
Pecorari Chiara,
Lee JiHoon,
Benassi Barbara,
Barilà Daniela,
Robert Caroline,
Stamler Jonathan S,
Cecconi Francesco,
Fraziano Maurizio,
Paull Tanya T,
Filomeni Giuseppe
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202050500
Subject(s) - library science , oxidative stress , political science , medicine , computer science
The denitrosylase S ‐nitrosoglutathione reductase (GSNOR) has been suggested to sustain mitochondrial removal by autophagy (mitophagy), functionally linking S ‐nitrosylation to cell senescence and aging. In this study, we provide evidence that GSNOR is induced at the translational level in response to hydrogen peroxide and mitochondrial ROS. The use of selective pharmacological inhibitors and siRNA demonstrates that GSNOR induction is an event downstream of the redox‐mediated activation of ATM, which in turn phosphorylates and activates CHK2 and p53 as intermediate players of this signaling cascade. The modulation of ATM/GSNOR axis, or the expression of a redox‐insensitive ATM mutant influences cell sensitivity to nitrosative and oxidative stress, impairs mitophagy and affects cell survival. Remarkably, this interplay modulates T‐cell activation, supporting the conclusion that GSNOR is a key molecular effector of the antioxidant function of ATM and providing new clues to comprehend the pleiotropic effects of ATM in the context of immune function.