Abstract
Neurotoxicity of human immunodeficiency virus-1 (HIV) includes synaptic simplification and neuronal apoptosis. However, the mechanisms of HIV-associated neurotoxicity remain unclear, thus precluding an effective treatment of the neurological complications. The present study was undertaken to characterize novel mechanisms of HIV neurotoxicity that may explain how HIV subjects develop neuronal degeneration. Several neurodegenerative disorders are characterized by mitochondrial dysfunction; therefore, we hypothesized that HIV promotes mitochondrial damage. We first analyzed brains from HIV encephalitis (HIVE) by electron microscopy. Several sections of HIVE subjects contained enlarged and damaged mitochondria compared to brains from HIV subjects with no neurological complications. Similar pathologies were observed in mice overexpressing the HIV protein gp120, suggesting that this viral protein may be responsible for mitochondrial pathology found in HIVE. To gain more information about the cellular mechanisms of gp120 neurotoxicity, we exposed rat cortical neurons to gp120 and we determined cellular oxygen consumption rate, mitochondrial distribution, and trafficking. Our data show that gp120 evokes impairment in mitochondrial function and distribution. These data suggest that one of the mechanisms of HIV neurotoxicity includes altered mitochondrial dynamics in neurons.
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Acknowledgments
This work was supported by US National Institute of Health Grants NS079172 and NS074916 (to I.M.), AG043384, MH062962, MH5974 and MH83506 (to E.M.), NS083426-01 (to J.F.), MH096625 (to E.E.), and P30AI087714 (pilot award from DC D-CFAR to V.A.).
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Valeriya Avdoshina and Jerel Adam Fields have contributed equally to this work.
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Supplementary material 1 Rat cortical neurons were labeled with MitoTracker deep red for 15 min to visualize mitochondria prior to time-lapse imaging. Brightfield and MitoTracker fluorescence were used to follow mitochondrial movement in neuronal processes. Time-lapse interval (TLI) and total duration (TD) of time-lapse footage are indicated. A. Control neurons (UT). Please note that some mitochondria are continuously traveling along neuronal processes. B. Neurons exposed to gp120ADA (5 nM). Please note that mitochondria stop moving within 5–10 s after the addition of gp120 (indicated by asterisks). White arrows indicate neurite blebbing. (MP4 11229 kb)
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Avdoshina, V., Fields, J.A., Castellano, P. et al. The HIV Protein gp120 Alters Mitochondrial Dynamics in Neurons. Neurotox Res 29, 583–593 (2016). https://doi.org/10.1007/s12640-016-9608-6
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DOI: https://doi.org/10.1007/s12640-016-9608-6