Modulating H2O2 levels in live cells.

Abstract

Hydrogen peroxide (H2O2) creates a steep intracellular gradient across different subcellular compartments, resulting in variations in redox signaling activation that are dependent on the localization of the peroxide. This study therefore aimed to evaluate the impact of localized H2O2 production and scavenging within specific cellular compartments, namely peroxisomes and the nucleus, on cell proliferation and oxidative stress responses. Through the targeted expression of either DAAO or CAT, which produce and scavenge H2O2 respectively, the local oxidative environment within these organelles can be modulated. Targeted CAT expression increased the resistance against peroxide, highlighting the importance of localized increases in antioxidant capacity. We confirmed that supraphysiological concentrations of peroxisomal H2O2 can reach the nucleus and activate the DNA damage response (DDR), as shown by the activation of ATM and Chk1. Additionally, p62 stabilization indicated the induction of autophagy, though not specifically pexophagy, at more physiological concentrations of peroxide. These findings emphasize the importance of the spatial aspect of H2O2 production and scavenging, with implications for understanding oxidative stress-related diseases, including tumorigenesis.