Mitochondrial glutaminase release contributes to glutamate-mediated neurotoxicity during human immunodeficiency virus-1 infection

Changhai Tian, Lijun Sun, Beibei Jia, Kangmu Ma, Norman Curthoys, Jianqing Ding, Jialin C Zheng

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Human immunodeficiency virus (HIV) induces a neurological disease culminating in frank dementia referred to as HIV-associated dementia (HAD). Neurotoxins from HIV-1-infected and activated mononuclear phagocytes contribute to the neuropathogenesis of HAD. Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS) and functions through activation of multiple receptors. Excessive glutamate production by HIV-infected macrophages in HAD may contribute to neuronal injury. Our previous studies have suggested that mitochondrial glutaminase is responsible for the excessive production of glutamate. However, how HIV-1 infection regulates glutamate over-production remains unclear. In this study, we propose that HIV infection-induced oxidative stress contributes to mitochondrial glutaminase release, which results in the excessive production of glutamate and subsequent neuronal injury. We collected conditioned media from HIV-1 infected macrophages and analyzed glutamate concentration in the media by RPHPLC, and found that the cyclosporine A (CsA), an inhibitor of HIV-1 replication and mitochondrial permeability transition pore, and N-acetylcysteine (NAC), a remover of reactive oxygen species (ROS), not only blocked the excessive glutamate production, but also decreased the glutamate-mediated neurotoxicity. In addition, HIVinfection- induced ROS generation was accompanied with the excessive glutamate production, suggesting that oxidative stress was involved in glutamate regulation. Using the isolated rat brain mitochondria as an ex vivo model and over-expressing GFP-glutaminase fusion protein in mammalian cells as a cell model, we confirm oxidative stress-mediated mitochondrial glutaminase release during HIV-1 infection contributes to glutamate over-production and the subsequent neurotoxicity. These results may provide insight into HAD pathogenesis and a therapeutic strategy for HAD treatment.

Original languageEnglish (US)
Pages (from-to)619-628
Number of pages10
JournalJournal of Neuroimmune Pharmacology
Volume7
Issue number3
DOIs
StatePublished - Sep 1 2012

Fingerprint

Glutaminase
Virus Diseases
HIV-1
Glutamic Acid
AIDS Dementia Complex
HIV
Oxidative Stress
Dementia
Reactive Oxygen Species
Macrophages
Wounds and Injuries
Neurotoxins
Acetylcysteine
Phagocytes
Conditioned Culture Medium
Virus Replication
Cyclosporine
Neurotransmitter Agents
Mitochondria
Central Nervous System

Keywords

  • Glutamate and neurotoxicity
  • HIV-1 infection
  • Mitochondrial glutaminase
  • Oxidative stress

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

Cite this

Mitochondrial glutaminase release contributes to glutamate-mediated neurotoxicity during human immunodeficiency virus-1 infection. / Tian, Changhai; Sun, Lijun; Jia, Beibei; Ma, Kangmu; Curthoys, Norman; Ding, Jianqing; Zheng, Jialin C.

In: Journal of Neuroimmune Pharmacology, Vol. 7, No. 3, 01.09.2012, p. 619-628.

Research output: Contribution to journalArticle

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