Survival and cell death in cells constitutively unable to synthesize glutathione

Mahara Valverde, Emilio Rojas, Subbarao V. Kala, Geeta Kala, Michael W. Lieberman

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

We examined the role of GSH in survival and cell death using GCS-2 cells that are deficient in glutamate cysteine ligase (γ-glutamyl cysteine synthetase, γGCS), an enzyme essential for GSH synthesis. Cells maintained in 2.5 mM GSH have GSH levels that are ∼2% of wild type and grow indefinitely; however, they express both pro- and anti-apoptotic Bcl-2 family members and have detectable levels of cytoplasmic cytochrome C. Withdrawal of GSH from the medium results in a fall in intracellular GSH to undetectable levels, decreased mitochondrial dehydrogenase activity, decreased anti-apoptotic factor RNAs, increased pro-apoptoic factor RNAs, additional cytochrome C release, and a fall in ATP levels; however, cells continue to grow for another 24 h. At 48 h, these trends continue with the exception that mitochondrial membrane potential and ATP levels rise; DNA fragmentation begins at 48 h. Thus, severe reduction of GSH to 2% of wild type produces a metastable state compatible with survival, but complete absence of GSH triggers apoptosis.

Original languageEnglish (US)
Pages (from-to)172-180
Number of pages9
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume594
Issue number1-2
DOIs
StatePublished - Feb 22 2006

Keywords

  • Apoptosis
  • Cell death
  • Glutamate cysteine ligase (γ-glutamyl cysteinyl synthetase) deficiency
  • Glutathione

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Molecular Biology

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