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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Aquaro S, Muscoli C, Ranazzi A, Pollicita M, Granato T, Masuelli L, Modesti A, Perno CF, Mollace V (2007) The contribution of peroxynitrite generation in HIV replication in human primary macrophages. Retrovirology 4:76. doi:10.1186/1742-4690-4-76
Argyropoulos C, Mouzaki A (2006) Immunosuppressive drugs in HIV disease. Curr Top Med Chem 6(16):1769–1789
Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD (2007) Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol 9(5):550–555. doi:10.1038/ncb1575
Borel JF (1976) Comparative study of in vitro and in vivo drug effects on cell-mediated cytotoxicity. Immunology 31(4):631–641
Borel JF, Feurer C, Gubler HU, Stahelin H (1976) Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 6(4):468–475
Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125(7):1241–1252
Curthoys NP, Watford M (1995) Regulation of glutaminase activity and glutamine metabolism. Annu Rev Nutr 15:133–159. doi:10.1146/annurev.nu.15.070195.001025
De Pinto VD, Palmieri F (1992) Transmembrane arrangement of mitochondrial porin or voltage-dependent anion channel (VDAC). J Bioenerg Biomembr 24(1):21–26
Derdeyn CA, Decker JM, Sfakianos JN, Wu X, O’Brien WA, Ratner L, Kappes JC, Shaw GM, Hunter E (2000) Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120. J Virol 74(18):8358–8367
Desagher S, Martinou JC (2000) Mitochondria as the central control point of apoptosis. Trends Cell Biol 10(9):369–377
Elbim C, Pillet S, Prevost MH, Preira A, Girard PM, Rogine N, Matusani H, Hakim J, Israel N, Gougerot-Pocidalo MA (1999) Redox and activation status of monocytes from human immunodeficiency virus-infected patients: relationship with viral load. J Virol 73(6):4561–4566
Erdmann N, Tian C, Huang Y, Zhao J, Herek S, Curthoys N, Zheng J (2009) In vitro glutaminase regulation and mechanisms of glutamate generation in HIV-1-infected macrophage. J Neurochem 109(2):551–561. doi:10.1111/j.1471-4159.2009.05989.x
Erdmann N, Zhao J, Lopez AL, Herek S, Curthoys N, Hexum TD, Tsukamoto T, Ferraris D, Zheng J (2007) Glutamate production by HIV-1 infected human macrophage is blocked by the inhibition of glutaminase. J Neurochem 102(2):539–549. doi:10.1111/j.1471-4159.2007.04594.x
Ferrarese C, Aliprandi A, Tremolizzo L, Stanzani L, De Micheli A, Dolara A, Frattola L (2001) Increased glutamate in CSF and plasma of patients with HIV dementia. Neurology 57(4):671–675
Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458(7239):762–765. doi:10.1038/nature07823
Gendelman HE, Orenstein JM, Martin MA, Ferrua C, Mitra R, Phipps T, Wahl LA, Lane HC, Fauci AS, Burke DS et al (1988) Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes. J Exp Med 167(4):1428–1441
Ghorpade A, Holter S, Borgmann K, Persidsky R, Wu L (2003) HIV-1 and IL-1 beta regulate Fas ligand expression in human astrocytes through the NF-kappa B pathway. J Neuroimmunol 141(1–2):141–149
Hess AD, Colombani PM, Esa AH (1986) Cyclosporine and the immune response: basic aspects. Crit Rev Immunol 6(2):123–149
Holcomb T, Taylor L, Trohkimoinen J, Curthoys NP (2000) Isolation, characterization and expression of a human brain mitochondrial glutaminase cDNA. Brain Res Mol Brain Res 76(1):56–63
Huang Y, Zhao L, Jia B, Wu L, Li Y, Curthoys N, Zheng JC (2011) Glutaminase dysregulation in HIV-1-infected human microglia mediates neurotoxicity: relevant to HIV-1-associated neurocognitive disorders. J Neurosci 31(42):15195–15204. doi:10.1523/JNEUROSCI.2051-11.2011
Jiang ZG, Piggee C, Heyes MP, Murphy C, Quearry B, Bauer M, Zheng J, Gendelman HE, Markey SP (2001) Glutamate is a mediator of neurotoxicity in secretions of activated HIV-1-infected macrophages. J Neuroimmunol 117(1–2):97–107
Kanno T, Sato EE, Muranaka S, Fujita H, Fujiwara T, Utsumi T, Inoue M, Utsumi K (2004) Oxidative stress underlies the mechanism for Ca(2+)-induced permeability transition of mitochondria. Free Radic Res 38(1):27–35
Kaul M (2009) HIV-1 associated dementia: update on pathological mechanisms and therapeutic approaches. Curr Opin Neurol 22(3):315–320. doi:10.1097/WCO.0b013e328329cf3c
Kaul M, Zheng J, Okamoto S, Gendelman HE, Lipton SA (2005) HIV-1 infection and AIDS: consequences for the central nervous system. Cell Death Differ 12(Suppl 1):878–892. doi:10.1038/sj.cdd.4401623
Kaul R, Rowland-Jones SL, Kimani J, Fowke K, Dong T, Kiama P, Rutherford J, Njagi E, Mwangi F, Rostron T, Onyango J, Oyugi J, MacDonald KS, Bwayo JJ, Plummer FA (2001) New insights into HIV-1 specific cytotoxic T-lymphocyte responses in exposed, persistently seronegative Kenyan sex workers. Immunol Lett 79(1–2):3–13
Kimura T, Kameoka M, Ikuta K (1993) Amplification of superoxide anion generation in phagocytic cells by HIV-1 infection. FEBS Lett 326(1–3):232–236
Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS (1986) Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233(4768):1089–1093
Le Bras M, Clement MV, Pervaiz S, Brenner C (2005) Reactive oxygen species and the mitochondrial signaling pathway of cell death. Histol Histopathol 20(1):205–219
Zhao L, Huang Y, Tian C, Taylor L, Curthoys N, Wang Y, Vernon H, Zheng J (2012) Interferon-α regulates glutaminase 1 promoter through STAT1 phosphorylation: Relevance to HIV-1 associated neurocognitive disorders. PLoS One (In Press)
Marozsan AJ, Fraundorf E, Abraha A, Baird H, Moore D, Troyer R, Nankja I, Arts EJ (2004) Relationships between infectious titer, capsid protein levels, and reverse transcriptase activities of diverse human immunodeficiency virus type 1 isolates. J Virol 78(20):11130–11141. doi:10.1128/JVI.78.20.11130-11141.2004
Marzo I, Brenner C, Kroemer G (1998) The central role of the mitochondrial megachannel in apoptosis: evidence obtained with intact cells, isolated mitochondria, and purified protein complexes. Biomed Pharmacother 52(6):248–251. doi:10.1016/S0753-3322(98)80009-7
Pan J, Chang Q, Wang X, Son Y, Zhang Z, Chen G, Luo J, Bi Y, Chen F, Shi X (2010) Reactive oxygen species-activated Akt/ASK1/p38 signaling pathway in nickel compound-induced apoptosis in BEAS 2B cells. Chem Res Toxicol 23(3):568–577. doi:10.1021/tx9003193
Peshavariya HM, Dusting GJ, Selemidis S (2007) Analysis of dihydroethidium fluorescence for the detection of intracellular and extracellular superoxide produced by NADPH oxidase. Free Radic Res 41(6):699–712. doi:10.1080/10715760701297354
Price TO, Uras F, Banks WA, Ercal N (2006) A novel antioxidant N-acetylcysteine amide prevents gp120- and Tat-induced oxidative stress in brain endothelial cells. Exp Neurol 201(1):193–202. doi:10.1016/j.expneurol.2006.03.030
Qin G, Meng X, Wang Q, Tian S (2009) Oxidative damage of mitochondrial proteins contributes to fruit senescence: a redox proteomics analysis. J Proteome Res 8(5):2449–2462. doi:10.1021/pr801046m
Robertson CL, Soane L, Siegel ZT, Fiskum G (2006) The potential role of mitochondria in pediatric traumatic brain injury. Dev Neurosci 28(4–5):432–446
Sokolskaja E, Olivari S, Zufferey M, Strambio-De-Castillia C, Pizzato M, Luban J (2010) Cyclosporine blocks incorporation of HIV-1 envelope glycoprotein into virions. J Virol 84(9):4851–4855. doi:10.1128/JVI.01699-09
Tian C, Erdmann N, Zhao J, Cao Z, Peng H, Zheng J (2008a) HIV-infected macrophages mediate neuronal apoptosis through mitochondrial glutaminase. J Neurochem 105(3):994–1005. doi:10.1111/j.1471-4159.2007.05197.x
Tian C, Gao P, Zheng Y, Yue W, Wang X, Jin H, Chen Q (2008b) Redox status of thioredoxin-1 (TRX1) determines the sensitivity of human liver carcinoma cells (HepG2) to arsenic trioxide-induced cell death. Cell Res 18(4):458–471. doi:10.1038/cr.2007.112
Wei X, Decker JM, Liu H, Zhang Z, Arani RB, Kilby JM, Saag MS, Wu X, Shaw GM, Kappes JC (2002) Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 46(6):1896–1905
Yang J, Su Y, Richmond A (2007) Antioxidants tiron and N-acetyl-L-cysteine differentially mediate apoptosis in melanoma cells via a reactive oxygen species-independent NF-kappaB pathway. Free Radic Biol Med 42(9):1369–1380. doi:10.1016/j.freeradbiomed.2007.01.036
Zhao J, Lopez AL, Erichsen D, Herek S, Cotter RL, Curthoys NP, Zheng J (2004) Mitochondrial glutaminase enhances extracellular glutamate production in HIV-1-infected macrophages: linkage to HIV-1 associated dementia. J Neurochem 88(1):169–180
Zheng J, Gendelman HE (1997) The HIV-1 associated dementia complex: a metabolic encephalopathy fueled by viral replication in mononuclear phagocytes. Curr Opin Neurol 10(4):319–325
Zheng J, Thylin MR, Cotter RL, Lopez AL, Ghorpade A, Persidsky Y, Xiong H, Leisman GB, Che MH, Gendelman HE (2001a) HIV-1 infected and immune competent mononuclear phagocytes induce quantitative alterations in neuronal dendritic arbor: relevance for HIV-1-associated dementia. Neurotox Res 3(5):443–459
Zheng J, Thylin MR, Persidsky Y, Williams CE, Cotter RL, Zink W, Ryan L, Ghorpade A, Lewis K, Gendelman HE (2001b) HIV-1 infected immune competent mononuclear phagocytes influence the pathways to neuronal demise. Neurotox Res 3(5):461–484
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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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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DOI: https://doi.org/10.1007/s11481-012-9364-1