Abstract
Glutathione reductase (GSR), a key member of the glutathione antioxidant defense system, converts oxidized glutathione (GSSG) to reduced glutathione (GSH) and maintains the intracellular glutathione redox state to protect the cells from oxidative damage. Previous reports have shown that Gsr deficiency results in defects in host defense against bacterial infection, while diquat induces renal injury in Gsr hypomorphic mice. In flies, overexpression of GSR extended lifespan under hyperoxia. In the current study, we investigated the roles of GSR in cochlear antioxidant defense using Gsr homozygous knockout mice that were backcrossed onto the CBA/CaJ mouse strain, a normal-hearing strain that does not carry a specific Cdh23 mutation that causes progressive hair cell degeneration and early onset of hearing loss. Gsr-/- mice displayed a significant decrease in GSR activity and GSH/GSSG ratios in the cytosol of the inner ears. However, Gsr deficiency did not affect ABR (auditory brainstem response) hearing thresholds, wave I amplitudes or wave I latencies in young mice. No histological abnormalities were observed in the cochlea of Gsr-/- mice. Furthermore, there were no differences in the activities of cytosolic glutathione-related enzymes, including glutathione peroxidase and glutamate-cysteine ligase, or the levels of oxidative damage markers in the inner ears between WT and Gsr-/- mice. In contrast, Gsr deficiency resulted in increased activities of cytosolic thioredoxin and thioredoxin reductase in the inner ears. Therefore, under normal physiological conditions, GSR is not essential for the maintenance of antioxidant defenses in mouse cochlea. Given that the thioredoxin system is known to reduce GSSG to GSH in multiple species, our findings suggest that the thioredoxin system can support GSSG reduction in the mouse peripheral auditory system.
Highlights
The antioxidant defenses consist of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX) and peroxiredoxin, and low-molecular weight antioxidants such as glutathione [1]
We have demonstrated that GSR is not required for cochlear development and function in young mice
We found that Gsr homozygous knockout mice are viable and appear normal
Summary
The antioxidant defenses consist of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX) and peroxiredoxin, and low-molecular weight antioxidants such as glutathione [1]. Glutathione (γ-glutamyl-cysteinyl-glycine) plays important roles in antioxidant defense and protects cells from ROS (reactive oxygen species) [2,3,4]. The GSH/ GSSG redox couple is thought to be an intracellular determinant of the antioxidant capacity because the abundance of GSH (~10–15 mM) is three to four orders of magnitude higher than the other reductants such as NADPH and reduced thioredoxin [4, 6]. GSH scavenges ROS through serving as a co-factor for GPX. In such reactions, GSH is oxidized to GSSG, which is reduced back to GSH by glutathione reductase (GSR) [3, 7, 8]. GSH plays an important role in detoxifying toxic chemicals by serving as a co-factor for glutathione transferase (GST) [9, 10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
