Glutathione metabolism in cobalamin deficiency type C (cblC)

Pastore, Anna; Martinelli, Diego; Piemonte, Fiorella; Tozzi, Giulia; Boenzi, Sara; Giovamberardino, Gianna Di; Petrillo, Sara; Bertini, Enrico; Dionisi‐Vici, Carlo

doi:10.1007/s10545-013-9605-3

Cited by 54 publications

(49 citation statements)

References 26 publications

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“…By promoting futile cycling, the Arg-161 mutants lead to enhanced O 2 . and GSSG formation, contributing to oxidative stress observed in fibroblasts (26) and increased GSSG levels seen in lymphocytes from cblC patients (40).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, cblC patients exhibit high levels of oxidative damage biomarkers, and human cblC fibroblasts have elevated levels of ROS (26,38). Furthermore, an imbalance in GSH metabolism with a significant decrease in GSH and an increase in GSSG concentration has been reported in CblC-deficient individuals (40). Although limited qualitative analyses of R161Q CblC have revealed impaired GSH-dependent MeCbl dealkylation activity (24), they have not provided insights into elevated ROS forma- (red trace, B).…”

Section: Discussionmentioning

confidence: 99%

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Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

Gherasim

Ruetz

et al. 2015

Journal of Biological Chemistry

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Background: CblC processes cobalamins entering a cell to a common intermediate. Results:Pathogenic mutations at Arg-161 weaken glutathione binding to CblC and stabilize cob(II)alamin. Conclusion: The R161Q/G mutations impair the dealkylation but not the decyanation activity of CblC. Significance: Increased redox cycling by the CblC mutants explains the observed cellular oxidative stress associated with this disorder.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

Gherasim

Ruetz

et al. 2015

Journal of Biological Chemistry

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“…Normal tissue levels range from approximately 0.1 mM to 10 mM, with the highest concentrations reported in liver, spleen, kidney, lens, erythrocytes and leukocytes [18]. Blood GSH levels have been considered to reflect the overall body GSH status, and hence are a potential indication of disease risk in humans [18]–[22]. Low glutathione concentrations are present in muscle samples obtained from individuals with primary mitochondrial disease [23].…”

Section: Introductionmentioning

confidence: 99%

“…Low glutathione concentrations are present in muscle samples obtained from individuals with primary mitochondrial disease [23]. Glutathione deficiency has also been reported in a variety of disorders associated with impaired mitochondrial function, including Friedreich ataxia [20], Leigh syndrome [21], organic acidemias [22], [24], and neurological disorders such as Alzheimer disease [25], Parkinson disease [26] and amyotropic lateral sclerosis [27]. These studies support the idea that glutathione levels may be a useful indicator of overall redox balance, and that this metric may give insights into various types of mitochondrial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Degree of Glutathione Deficiency and Redox Imbalance Depend on Subtype of Mitochondrial Disease and Clinical Status

Enns

Moore

et al. 2014

PLoS ONE

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Mitochondrial disorders are associated with decreased energy production and redox imbalance. Glutathione plays a central role in redox signaling and protecting cells from oxidative damage. In order to understand the consequences of mitochondrial dysfunction on in vivo redox status, and to determine how this varies by mitochondrial disease subtype and clinical severity, we used a sensitive tandem mass spectrometry assay to precisely quantify whole blood reduced (GSH) and oxidized (GSSG) glutathione levels in a large cohort of mitochondrial disorder patients. Glutathione redox potential was calculated using the Nernst equation. Compared to healthy controls (n = 59), mitochondrial disease patients (n = 58) as a group showed significant redox imbalance (redox potential −251 mV±9.7, p<0.0001) with an increased level of oxidation by ∼9 mV compared to controls (−260 mV±6.4). Underlying this abnormality were significantly lower whole blood GSH levels (p = 0.0008) and GSH/GSSG ratio (p = 0.0002), and significantly higher GSSG levels (p<0.0001) in mitochondrial disease patients compared to controls. Redox potential was significantly more oxidized in all mitochondrial disease subgroups including Leigh syndrome (n = 15), electron transport chain abnormalities (n = 10), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (n = 8), mtDNA deletion syndrome (n = 7), mtDNA depletion syndrome (n = 7), and miscellaneous other mitochondrial disorders (n = 11). Patients hospitalized in metabolic crisis (n = 7) showed the greatest degree of redox imbalance at −242 mV±7. Peripheral whole blood GSH and GSSG levels are promising biomarkers of mitochondrial dysfunction, and may give insights into the contribution of oxidative stress to the pathophysiology of the various mitochondrial disorders. In particular, evaluation of redox potential may be useful in monitoring of clinical status or response to redox-modulating therapies in clinical trials.

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“…Apart from the above described characteristics, cystinosis renal epithelial cells exhibit an increased concentration of oxidized glutathione (GSSG), and supplementation with cysteamine (1mM) restored levels of reduced glutathione (GSH), thus repairing GSH/GSSG homeostasis (Wilmer et al 2011). Deficiencies of glutathione appear to be common among inherited diseases (Abeti et al 2016, Caterino et al 2015, Pastore et al 2014, Petrillo et al 2013). Therefore, it is possible that the benefits of cysteamine may extend beyond its proposed targeting of cystine in cystinosis.…”

Section: Introductionmentioning

confidence: 99%

Cysteamine revisited: repair of arginine to cysteine mutations

Gallego

Hannibal

Häberle

et al. 2017

J of Inher Metab Disea

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Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides “proof of principle” that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since Arg to Cys changes comprise in general about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.

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Glutathione metabolism in cobalamin deficiency type C (cblC)

Cited by 54 publications

References 26 publications

Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

Degree of Glutathione Deficiency and Redox Imbalance Depend on Subtype of Mitochondrial Disease and Clinical Status

Cysteamine revisited: repair of arginine to cysteine mutations

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