Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicity

V. B.R. Pichili, K. V. Rama Rao, A. R. Jayakumar, Michael D. Norenberg

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Hepatic encephalopathy (HE) is a major neurological complication that occurs in the setting of severe liver failure. Ammonia is a key neurotoxin implicated in this condition, and astrocytes are the principal neural cells histopathologically and functionally affected. Although the mechanism by which ammonia causes astrocyte dysfunction is incompletely understood, glutamine, a by-product of ammonia metabolism, has been strongly implicated in many of the deleterious effects of ammonia on astrocytes. Inhibiting mitochondrial glutamine hydrolysis in astrocytes mitigates many of the toxic effects of ammonia, suggesting the involvement of mitochondrial glutamine metabolism in the mechanism of ammonia neurotoxicity. To determine whether mitochondria are indeed the organelle where glutamine exerts its toxic effects, we examined the effect of L-histidine, an inhibitor of mitochondrial glutamine transport, on ammonia-mediated astrocyte defects. Treatment of cultured astrocytes with L-histidine completely blocked or significantly attenuated ammonia-induced reactive oxygen species production, cell swelling, mitochondrial permeability transition, and loss of ATP. These findings implicate mitochondrial glutamine transport in the mechanism of ammonia neurotoxicity.

Original languageEnglish (US)
Pages (from-to)801-809
Number of pages9
JournalGlia
Volume55
Issue number8
DOIs
StatePublished - Jun 1 2007

    Fingerprint

Keywords

  • Ammonia
  • Astrocytes
  • ATP
  • Free radicals
  • Glutamine
  • Hepatic encephalopathy
  • Histidine
  • Mitochondrial permeability transition
  • Phosphate-activated glutaminase

ASJC Scopus subject areas

  • Immunology

Cite this