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HIV-infected macrophages mediate neuronal apoptosis through mitochondrial glutaminase
Changhai Tian1, Nathan Erdmann, Jianxing Zhao
1Laboratory of Neurotoxicology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5880, USA.
Abstract:
A significant number of patients infected with human immunodeficiency virus-1 (HIV-1) suffer cognitive impairment ranging from mild to severe HIV-associated dementia (HAD), a result of neuronal degeneration in the basal ganglia, cerebral cortex and hippocampus. Mononuclear phagocyte dysfunction is thought to play an important role in the pathogenesis of HAD. Glutamate neurotoxicity is triggered primarily by massive Ca2+ influx arising from over-stimulation of the NMDA subtype of glutamate receptors. The underlying mechanisms, however, remain elusive. We have tested the hypothesis that mitochondrial glutaminase in HIV-infected macrophages is involved in converting glutamine to glutamate. Our results demonstrate that the concentration of glutamate in HIV-1 infected conditioned media was dependent on glutamine dose, and HIV-1 infected conditioned medium mediated glutamine-dependent neurotoxicity. These results indicate HIV-infection mediates neurotoxicity through glutamate production. In addition, glutamate-mediated neurotoxicity correlated with caspase activation and neuronal cell cycle re-activation. Inhibition of mitochondrial glutaminase diminished the HIV-induced glutamate production, and attenuated NMDA over-stimulation and subsequent neuronal apoptosis. These data implicate mitochondrial glutaminase in the induction of glutamate-mediated neuronal apoptosis during HIV-associated dementia, and provides a possible therapeutic strategy for HAD treatment.
Insights
HIV-1 infection causes cognitive impairment by increasing glutamate production in macrophages, leading to neuronal damage. Inhibiting mitochondrial glutaminase may offer a therapeutic strategy for HIV-associated dementia.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Human Immunodeficiency Virus-1 (HIV-1) infection is linked to significant cognitive impairment, including HIV-associated dementia (HAD).
- Neuronal degeneration in key brain regions and mononuclear phagocyte dysfunction are implicated in HAD pathogenesis.
- Glutamate neurotoxicity, driven by NMDA receptor over-stimulation and calcium influx, is a suspected mechanism, but its precise role remains unclear.
Purpose of the Study:
- To investigate the role of mitochondrial glutaminase in HIV-infected macrophages in the context of neurotoxicity.
- To test the hypothesis that HIV-infected macrophages produce excess glutamate, contributing to neuronal damage.
Main Methods:
- Assessed glutamate concentration in conditioned media from HIV-1 infected macrophages.
- Evaluated the neurotoxic effects of this conditioned media on neuronal cells.
- Measured caspase activation and neuronal cell cycle re-activation.
- Investigated the impact of inhibiting mitochondrial glutaminase on glutamate production and neurotoxicity.
Main Results:
- HIV-1 infected macrophages produced glutamate in a dose-dependent manner related to glutamine availability.
- Conditioned media from HIV-1 infected cells induced glutamine-dependent neurotoxicity.
- This neurotoxicity correlated with increased caspase activation and neuronal cell cycle re-activation.
- Inhibiting mitochondrial glutaminase reduced HIV-induced glutamate production and attenuated NMDA receptor over-stimulation and neuronal apoptosis.
Conclusions:
- HIV-1 infection promotes glutamate production via mitochondrial glutaminase in macrophages.
- This HIV-induced glutamate contributes to NMDA receptor over-stimulation and subsequent neuronal apoptosis, a key factor in HAD.
- Targeting mitochondrial glutaminase presents a potential therapeutic avenue for managing HIV-associated dementia.
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