Abstract
Background: Genetically defined Leigh syndrome (LS) is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. Although mitochondrial dysfunction has clearly been associated with oxidative stress, few studies have specifically examined Leigh syndrome patients' blood glutathione levels. In this study, we analyzed the balance between oxidized and reduced glutathione in lymphocytes of 10 patients with genetically confirmed LS and monitored the effects of glutathione status following 6. months of treatment with EPI-743, a novel redox therapeutic. Methods: Lymphocytes were obtained from blood samples of 10 children with a genetically confirmed diagnosis of LS and in 20 healthy subjects. Total, reduced, oxidized and protein-bound glutathione levels were determined by HPLC analysis. Erythrocyte superoxide dismutase and glutathione peroxidase enzyme activities were measured by spectrophotometric assays. Plasma total thiols, carbonyl contents and malondialdehyde were assessed by spectrophotometric and fluorometric assays. Results: A significant impairment of all glutathione forms was detected in patients, including a profound decrease of total and reduced glutathione (GSH) associated with high levels of all oxidized glutathione forms (GSSG. +. GS-Pro; OX). These findings negatively correlated with the glutathione peroxidase activity, which underwent a significant decrease in patients. After treatment with EPI-743, all patients showed a significant increase in reduced glutathione levels and 96% decrease of OX/GSH ratio. Conclusions: The data presented here strongly support glutathione as a "redox blood signature" in mitochondrial disorders and its use as a clinical trial endpoint in the development of mitochondrial disease therapies.
| Original language | English |
|---|---|
| Pages (from-to) | 208-214 |
| Number of pages | 7 |
| Journal | Molecular Genetics and Metabolism |
| Volume | 109 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Jun 2013 |
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Keywords
- EPI-743
- Glutathione
- Leigh syndrome
- Mitochondrial encephalomyopathies
- Oxidative stress
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Genetics
- Endocrinology
- Endocrinology, Diabetes and Metabolism
Cite this
Glutathione : A redox signature in monitoring EPI-743 therapy in children with mitochondrial encephalomyopathies. / Pastore, Anna; Petrillo, Sara; Tozzi, Giulia; Carrozzo, Rosalba; Martinelli, Diego; Dionisi-Vici, Carlo; Di Giovamberardino, Gianna; Ceravolo, Ferdinando; Klein, Matthew B.; Miller, Guy; Enns, Gregory M.; Bertini, Enrico; Piemonte, Fiorella.
In: Molecular Genetics and Metabolism, Vol. 109, No. 2, 06.2013, p. 208-214.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Glutathione
T2 - A redox signature in monitoring EPI-743 therapy in children with mitochondrial encephalomyopathies
AU - Pastore, Anna
AU - Petrillo, Sara
AU - Tozzi, Giulia
AU - Carrozzo, Rosalba
AU - Martinelli, Diego
AU - Dionisi-Vici, Carlo
AU - Di Giovamberardino, Gianna
AU - Ceravolo, Ferdinando
AU - Klein, Matthew B.
AU - Miller, Guy
AU - Enns, Gregory M.
AU - Bertini, Enrico
AU - Piemonte, Fiorella
PY - 2013/6
Y1 - 2013/6
N2 - Background: Genetically defined Leigh syndrome (LS) is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. Although mitochondrial dysfunction has clearly been associated with oxidative stress, few studies have specifically examined Leigh syndrome patients' blood glutathione levels. In this study, we analyzed the balance between oxidized and reduced glutathione in lymphocytes of 10 patients with genetically confirmed LS and monitored the effects of glutathione status following 6. months of treatment with EPI-743, a novel redox therapeutic. Methods: Lymphocytes were obtained from blood samples of 10 children with a genetically confirmed diagnosis of LS and in 20 healthy subjects. Total, reduced, oxidized and protein-bound glutathione levels were determined by HPLC analysis. Erythrocyte superoxide dismutase and glutathione peroxidase enzyme activities were measured by spectrophotometric assays. Plasma total thiols, carbonyl contents and malondialdehyde were assessed by spectrophotometric and fluorometric assays. Results: A significant impairment of all glutathione forms was detected in patients, including a profound decrease of total and reduced glutathione (GSH) associated with high levels of all oxidized glutathione forms (GSSG. +. GS-Pro; OX). These findings negatively correlated with the glutathione peroxidase activity, which underwent a significant decrease in patients. After treatment with EPI-743, all patients showed a significant increase in reduced glutathione levels and 96% decrease of OX/GSH ratio. Conclusions: The data presented here strongly support glutathione as a "redox blood signature" in mitochondrial disorders and its use as a clinical trial endpoint in the development of mitochondrial disease therapies.
AB - Background: Genetically defined Leigh syndrome (LS) is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. Although mitochondrial dysfunction has clearly been associated with oxidative stress, few studies have specifically examined Leigh syndrome patients' blood glutathione levels. In this study, we analyzed the balance between oxidized and reduced glutathione in lymphocytes of 10 patients with genetically confirmed LS and monitored the effects of glutathione status following 6. months of treatment with EPI-743, a novel redox therapeutic. Methods: Lymphocytes were obtained from blood samples of 10 children with a genetically confirmed diagnosis of LS and in 20 healthy subjects. Total, reduced, oxidized and protein-bound glutathione levels were determined by HPLC analysis. Erythrocyte superoxide dismutase and glutathione peroxidase enzyme activities were measured by spectrophotometric assays. Plasma total thiols, carbonyl contents and malondialdehyde were assessed by spectrophotometric and fluorometric assays. Results: A significant impairment of all glutathione forms was detected in patients, including a profound decrease of total and reduced glutathione (GSH) associated with high levels of all oxidized glutathione forms (GSSG. +. GS-Pro; OX). These findings negatively correlated with the glutathione peroxidase activity, which underwent a significant decrease in patients. After treatment with EPI-743, all patients showed a significant increase in reduced glutathione levels and 96% decrease of OX/GSH ratio. Conclusions: The data presented here strongly support glutathione as a "redox blood signature" in mitochondrial disorders and its use as a clinical trial endpoint in the development of mitochondrial disease therapies.
KW - EPI-743
KW - Glutathione
KW - Leigh syndrome
KW - Mitochondrial encephalomyopathies
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=84878490948&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878490948&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2013.03.011
DO - 10.1016/j.ymgme.2013.03.011
M3 - Article
VL - 109
SP - 208
EP - 214
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
SN - 1096-7192
IS - 2
ER -