Glutamate and glutathione interplay in a motor neuronal model of amyotrophic lateral sclerosis reveals altered energy metabolism

Giuseppina D'Alessandro, Eleonora Calcagno, Silvia Tartari, Milena Rizzardini, Roberto William Invernizzi, Lavinia Cantoni

Research output: Contribution to journalArticle

Abstract

Impairment of mitochondrial function might contribute to oxidative stress associated with neurodegeneration in amyotrophic lateral sclerosis (ALS). Glutamate levels in tissues of ALS patients are sometimes altered. In neurons, mitochondrial metabolism of exogenous glutamine is mainly responsible for the net synthesis of glutamate, which is a neurotransmitter, but it is also necessary for the synthesis of glutathione, the main endogenous antioxidant. We investigated glutathione synthesis and glutamine/glutamate metabolism in a motor neuronal model of familial ALS. In standard culture conditions (with glutamine) or restricting glutamine or cystine, the level of glutathione was always lower in the cell line expressing the mutant (G93A) human Cu, Zn superoxide dismutase (G93ASOD1) than in the line expressing wild-type SOD1. With glutamine the difference in glutathione was associated with a lower glutamate and impairment of the glutamine/glutamate metabolism as evidenced by lower glutaminase and cytosolic malate dehydrogenase activity. d-β-hydroxybutyrate, as an alternative to glutamine as energy substrate in addition to glucose, reversed the decreases of cytosolic malate dehydrogenase activity and glutamate and glutathione. However, in the G93ASOD1 cell line, in all culture conditions the expression of pyruvate dehydrogenase kinase l protein, which down-regulates pyruvate dehydrogenase activity, was induced, together with an increase in lactate release in the medium. These findings suggest that the glutathione decrease associated with mutant SOD1 expression is due to mitochondrial dysfunction caused by the reduction of the flow of glucose-derived pyruvate through the TCA cycle; it implies altered glutamate metabolism and depends on the different mitochondrial energy substrates.

Original languageEnglish
Pages (from-to)346-355
Number of pages10
JournalNeurobiology of Disease
Volume43
Issue number2
DOIs
Publication statusPublished - Aug 2011

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Keywords

  • Amyotrophic lateral sclerosis
  • Cu,Zn superoxide dismutase
  • Glutamate
  • Glutaminase
  • Glutamine
  • Glutathione
  • Motor neuron
  • NSC-34 cells
  • Pyruvate dehydrogenase kinase l

ASJC Scopus subject areas

  • Neurology

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