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Mitochondrial Glutaminase Release Contributes to Glutamate-Mediated Neurotoxicity during Human Immunodeficiency Virus-1 Infection

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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 RP-HPLC, 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, HIV-infection-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.

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Acknowledgements

We kindly thank Dr. Terry D. Hexum for comments on the manuscript and Drs.Yunlong Huang, Hui Peng, Ling Ye, Lixia Zhao, Myhanh Che, Li Wu and Kristin Leland Wavrin, who provided support for this work. Julie Ditter, Lenal M Bottoms, Johna Belling, and Robin Taylor provided outstanding administrative and secretarial support. This work was supported in part by research grants by the National Institutes of Health: R01 NS 41858–01, R01 NS 061642–01, 3R01NS61642-2S1, R21 MH 083525–01, P01 NS043985, and P20 RR15635-01 (JZ) and National Natural Science Foundation of China (NSFC) # 81028007.

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Authors and Affiliations

  1. Department of Pharmacology/Experimental Neuroscience, Laboratory of Neuroimmunology and Regenerative Therapy, University of Nebraska Medical Center, 985930 Nebraska Medical Center, Omaha, NE, 68198-5930, USA

    Changhai Tian, Lijun Sun, Beibei Jia, Kangmu Ma & Jialin Zheng

  2. Department of Pathology/Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5930, USA

    Jialin Zheng

  3. Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, 80523, USA

    Norman Curthoys

  4. Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Jianqing Ding

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  1. Changhai Tian
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Correspondence to Jialin Zheng.

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Tian, C., Sun, L., Jia, B. et al. Mitochondrial Glutaminase Release Contributes to Glutamate-Mediated Neurotoxicity during Human Immunodeficiency Virus-1 Infection. J Neuroimmune Pharmacol 7, 619–628 (2012). https://doi.org/10.1007/s11481-012-9364-1

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