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Composition of the redox environment of the endoplasmic reticulum and sources of hydrogen peroxide

Margittai É1, Enyedi B2, Csala M3, Geiszt M4, Bánhegyi G5.

Free Radic Biol Med. 2015 . pii: S0891-5849(15)00039-8.

 

1Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest 1444, Hungary.

2Department of Physiology, Semmelweis University, Budapest 1444, Hungary.

3Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest 1444, Hungary.

4Department of Physiology, Semmelweis University, Budapest 1444, Hungary; “Lendület” Peroxidase Enzyme Research Group of Semmelweis University and the Hungarian Academy of Sciences, Semmelweis University, Budapest 1444, Hungary.

5Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest 1444, Hungary. Electronic address: [email protected]

Abstract

The endoplasmic reticulum (ER) is a metabolically active organelle, which has a central role in proteostasis by translating, modifying, folding, and occasionally degrading secretory and membrane proteins. The lumen of the ER represents a separate compartment of the eukaryotic cell, with a characteristic proteome and metabolome. Although the redox metabolome and proteome of the compartment have not been holistically explored, it is evident that proper redox conditions are necessary for the functioning of many luminal pathways. These redox conditions are defined by local oxidoreductases and the membrane transport of electron donors and acceptors. The main electron carriers of the compartment are identical with those of the other organelles: glutathione, pyridine and flavin nucleotides, ascorbate, and others. However, their composition, concentration, andredox state in the ER lumen can be different from those observed in other compartments. The terminal oxidases of oxidative protein folding generate and maintain an “oxidative environment” by oxidizing protein thiols and producing hydrogen peroxide. ER-specific mechanisms reutilize hydrogen peroxide as an electron acceptor of oxidative folding. These mechanisms, together with membrane and kinetic barriers, guarantee that redoxsystems in the reduced or oxidized state can be present simultaneously in the lumen. The present knowledge on the in vivo conditions of ER redoxis rather limited; development of new genetically encoded targetable sensors for the measurement of the luminal state of redox systems other than thiol/disulfide will contribute to a better understanding of ER redox homeostasis.

Copyright © 2015 Elsevier Inc. All rights reserved.

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Significance Statement

 The endoplasmic reticulum (ER) is the center and origin of the endomembrane system, and hence it is an obligatory organelle of the eukaryotic cell. ER-localized enzymes are involved in all branches of the intermediary metabolism and in biotransformation, yet the organelle is generally considered as a protein factory due to its widely studied role in protein synthesis and processing. Newly translated peptide chains are co-translationally translocated across the ER membrane, and their luminal segments undergo a unique maturation process. Disulfide bond formation is one of the typical post-translational modifications in the luminal compartment of the ER This oxidative protein folding is based on the partial reduction of molecular oxygen as an ultimate electron acceptor. Hydrogen peroxide is, therefore, continuously generated by the terminal oxidases of oxidative folding and presumably also by other local enzymes, e.g. NADPH oxidase 4, gulonolactone oxidase. However, hydrogen peroxide produced in the ER lumen is rather a powerful and useful than a harmful oxidant, and hence, unlike in other cellular compartments, it is utilized rather than just eliminated. Accordingly, the well-known hydrogen peroxide detoxifying antioxidant mechanisms are missing in the ER lumen, and H2O2 consumption is catalyzed by ER-specific enzymes such as peroxiredoxin 4 and glutathione peroxidase 7 and 8. These enzymes employ protein thiols as electron donors and hydrogen peroxide as an electron acceptor, thus furthering oxidative folding. The review summarizes the major mechanisms of hydrogen peroxide production and elimination in the ER lumen and their impact on the redox systems of the lumen. It also provides an overview on the currently available tools and methods applied for the measurement of ER luminal hydrogen peroxide. It is emphasized that a great improvement in the present understanding of ER redox homeostasis can be expected from in situ real time assessment of local redox conditions by using new recombinant targetable sensors, which are currently under development.

Figure Legend:

Utilization of hydrogen peroxide as electron acceptor in the oxidative folding in the endoplasmic reticulum.

Composition of the redox environment of the endoplasmic reticulum and sources of hydrogen peroxide