Glutathione

A redox signature in monitoring EPI-743 therapy in children with mitochondrial encephalomyopathies

Anna Pastore, Sara Petrillo, Giulia Tozzi, Rosalba Carrozzo, Diego Martinelli, Carlo Dionisi-Vici, Gianna Di Giovamberardino, Ferdinando Ceravolo, Matthew B. Klein, Guy Miller, Gregory M. Enns, Enrico Bertini, Fiorella Piemonte

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 languageEnglish
Pages (from-to)208-214
Number of pages7
JournalMolecular Genetics and Metabolism
Volume109
Issue number2
DOIs
Publication statusPublished - Jun 2013

Fingerprint

Mitochondrial Encephalomyopathies
Oxidation-Reduction
Glutathione
Leigh Disease
Monitoring
Glutathione Disulfide
Mitochondrial Diseases
Blood
Lymphocytes
Therapeutics
Glutathione Peroxidase
Assays
Oxidative stress
alpha-tocotrienol quinone
Enzyme activity
Malondialdehyde
Sulfhydryl Compounds
Neurodegenerative Diseases
Superoxide Dismutase
Healthy Volunteers

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 journalArticle

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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.",
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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

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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.

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