Genetic analysis of tissue glutathione concentrations and redox balance

Abstract

Glutathione redox balance ― defined as the ratio GSH/GSSG ― is a critical regulator of cellular redox state, and declines in this ratio are closely associated with oxidative stress and disease. However, little is known about the impact of genetic variation on this trait. Previous mouse studies suggest that tissue GSH/GSSG is regulated by genetic background and is therefore heritable. In this study, we measured glutathione concentrations and GSH/GSSG in liver and kidney of 30 genetically-diverse inbred mouse strains. Genetic background caused an approximately three-fold difference in hepatic and renal GSH/GSSG between the most disparate strains. Haplotype association mapping determined the loci associated with hepatic and renal glutathione phenotypes. We narrowed the number of significant loci by focusing on those located within protein-coding genes, which we now consider to be candidate genes for glutathione homeostasis. No candidate genes were associated with both hepatic and renal GSH/GSSG, suggesting that genetic regulation of GSH/GSSG occurs predominantly in a tissue-specific manner. This is the first quantitative trait loci study to examine the genetic regulation of glutathione concentrations and redox balance in mammals. We identified novel candidate genes that have the potential to redefine our knowledge of redox biochemistry, its regulation, and inform future therapeutic applications.

Basal levels of glutathione peroxidase correlate with onset of radiation induced lung disease in inbred mouse strains

“…Indeed GSH activity levels in the liver differing by threefold over a panel of strains have been reported (37), which is similar to the range in values measured here for the lung. The specific genetic differences among inbred strains that result in varied GSH levels are unknown at present, but recent studies have identified candidate genes for this trait based on association studies in mice (8,37). Finally, early levels of the primary radiation injury of ROS generation or oxidative stress were not strongly correlated with the later lung disease in mice.…”

“…In support of this finding, RBC catalase and GSH measures were independent of the pneumonitis response in radiotherapy patients (21), although high SOD was associated with pneumonitis in this group of patients. Regarding the strain dependence of the biomarkers, we are not aware of other studies documenting this variability for lung tissue, although multiple groups have reported inbred strain background to have a major effect on GSH levels in the liver (8,30,34,37) and the kidney (37), and on liver catalase levels (30). Indeed GSH activity levels in the liver differing by threefold over a panel of strains have been reported (37), which is similar to the range in values measured here for the lung.…”

“…Regarding the strain dependence of the biomarkers, we are not aware of other studies documenting this variability for lung tissue, although multiple groups have reported inbred strain background to have a major effect on GSH levels in the liver (8,30,34,37) and the kidney (37), and on liver catalase levels (30). Indeed GSH activity levels in the liver differing by threefold over a panel of strains have been reported (37), which is similar to the range in values measured here for the lung. The specific genetic differences among inbred strains that result in varied GSH levels are unknown at present, but recent studies have identified candidate genes for this trait based on association studies in mice (8,37).…”

Identification of CNVs in the Nelore genome and its association with meat tenderness

“…We also found two regions of polymorphic CNV (CNVR_2061 and 2443) that overlapped two QTLs for glutathione redox balance (ZHOU et al, 2014), which prompts further investigation as the glutathione dimer has been reported as a MTpredictor (D'ALESSANDRO et al, 2012a). Moreover, an overlapped gene mapped at those QTLs called SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) inhibits the transduction pathway of myostatin (ZHU et al, 2004).…”

“…Moreover, an overlapped gene mapped at those QTLs called SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) inhibits the transduction pathway of myostatin (ZHU et al, 2004). The chaperonin containing TCP1, subunit 6B (zeta 2) (CCT6B) gene was also mapped in glutathione redox balance QTLs (ZHOU et al, 2014). The chaperonins have an important role in protein folding process (SPIESS et al, 2004), which is very important in meat tenderization (LOMIWES et al, 2014).…”