Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress

Claudia Cirotti,Giuseppe Filomeni,Chiara Pecorari,Daniela Barilà,Maria Francesca Allega,Noemi Poerio,Ji‐Hoon Lee,Jonathan S Stamler,Giuseppina Claps,Salvatore Rizza,Tanya T Paull,Maurizio Fraziano,Paola Giglio,Barbara Benassi,Francesco Cecconi,Caroline Robert

doi:10.15252/embr.202050500

Abstract

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.

Highlights

The denitrosylase S-nitrosoglutathione reductase (GSNOR) has been suggested to sustain mitochondrial removal by autophagy, functionally linking S-nitrosylation to cell senescence and aging
We recently reported that the NADH-dependent denitrosylase Snitrosoglutathione reductase (GSNOR), by regulating the S-nitrosylation state of proteins involved in mitochondrial dynamics and mitophagy, sustains correct mitochondrial removal and delays cell
We hypothesized that, analogously to many antioxidant enzymes, GSNOR expression could be modulated in response to H2O2, whose intracellular concentration has frequently been found to increase in experimental models of aging (Sohal & Sohal, 1991; Balaban et al, 2005; Sohal & Orr, 2012)

Summary

Introduction

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. 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. 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.

Methods

Results

Conclusion