Intracellular Sources of ROS/H2O2 in Health and Neurodegeneration: Spotlight on Endoplasmic Reticulum.

Tasuku Konno,Edward Avezov,Eduardo Pinho Melo,Joseph E Chambers

doi:10.3390/cells10020233

Abstract

Reactive oxygen species (ROS) are produced continuously throughout the cell as products of various redox reactions. Yet these products function as important signal messengers, acting through oxidation of specific target factors. Whilst excess ROS production has the potential to induce oxidative stress, physiological roles of ROS are supported by a spatiotemporal equilibrium between ROS producers and scavengers such as antioxidative enzymes. In the endoplasmic reticulum (ER), hydrogen peroxide (H2O2), a non-radical ROS, is produced through the process of oxidative folding. Utilisation and dysregulation of H2O2, in particular that generated in the ER, affects not only cellular homeostasis but also the longevity of organisms. ROS dysregulation has been implicated in various pathologies including dementia and other neurodegenerative diseases, sanctioning a field of research that strives to better understand cell-intrinsic ROS production. Here we review the organelle-specific ROS-generating and consuming pathways, providing evidence that the ER is a major contributing source of potentially pathologic ROS.

Highlights

With an emphasis on the endoplasmic reticulum (ER), here we review the findings contributing to the current understanding of organelles’ reactive oxygen species (ROS) producing/consuming pathways and discuss how an imbalance in the activity of ROS generating and antagonising pathways as well as organellar ROS permeability dysregulation can lead to an increase in their steady-state load
This can reduce the accumulation of unfolded proteins and results in neuroprotection, whereas excess H2 O2, which is concomitantly produced by this process, exacerbates neurodegeneration as an oxidative stress agent
Utilises a ROS, H2 O2 to directly fuel is anabolic activity—the oxidative protein folding. This organelle satisfies its own demand of ROS by internally producing abundant H2 O2, on a scale that may well exceed that of any other organelle

Summary

Introduction

Substantial quantities of reactive oxygen species (ROS), H2 O2 in particular, are produced intracellularly. Besides PRDX4, ER H2 O2 is utilised by ER-resident glutathione peroxidases, GPX7 and GPX8 (ER luminal and lumen-facing membrane anchored, respectively [44]) Both can oxidise PDI in the presence of H2 O2 and interact with ERO1, catalysing oxidative protein folding [29,44,45]. When glutathione is depleted, levels of H2 O2 in the ER augment, and the viability of cells with reduced cytosolic antioxidant capacity (e.g., a pancreatic β-cell model, with natural catalase deficiency) becomes strongly compromised, when H2 O2 production is further stimulated through the biosynthesis of disulphide-containing substrates (e.g., pro-insulin) [13] This highlights the physiological relevance of the chemical reduction of H2 O2 by GSH and further suggests that the ER constitutes a significant source of pathological ROS

O2 Transport Across the ER Membrane

Findings

Conclusions and Perspectives