Impaired activity of the γ-glutamyl cycle in nephropathic cystinosis fibroblasts

Liliana Mannucci, Anna Pastore, Cristiano Rizzo, Fiorella Piemonte, Gianfranco Rizzoni, Francesco Emma

Research output: Contribution to journalArticlepeer-review


Cystinotic patients have been shown to excrete in their urine high levels of pyroglutamate, an intermediate metabolite of the adenosine triphosphate (ATP)-dependent γ-glutamyl cycle, which is responsible for glutathione (GSH) synthesis. Human fibroblasts were used to study the mechanisms leading to pyroglutamate accumulation in nephropathic cystinosis (NC). We show that inhibition of ATP synthesis caused a marked intracellular accumulation of pyroglutamate, reflecting decreased GSH synthesis. Despite similar degrees of ATP depletion, pyroglutamate increased more in cystinotic fibroblasts than in controls, while GSH decreased to lower levels. In addition, cystinotic cells exposed to oxidative stress (hydrogen peroxide) were unable to increase their GSH concentration above base-line. These results could not be attributed to differences in mitochondrial oxidative activity or to increased apoptotic cell death. Together, these results support the hypothesis that cysteine derived from lysosomal cystine efflux limits the activity of the γ-glutamyl cycle and GSH synthesis.

Original languageEnglish
Pages (from-to)332-335
Number of pages4
JournalPediatric Research
Issue number2
Publication statusPublished - Feb 2006

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health


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