Open AccessTCA cycle metabolic compromise due to an aberrant S-nitrosoproteome in HIV-associated neurocognitive disorder with methamphetamine use
Author(s) -
PaschalisThomas Doulias,
Tomohiro Nakamura,
Henry Scott,
Scott R. McKercher,
Abdullah Sultan,
Amanda Deal,
Matthew E. Albertolle,
Harry Ischiropoulos,
Stuart A. Lipton
Publication year - 2021
Publication title -
journal of neurovirology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.868
H-Index - 85
eISSN - 1538-2443
pISSN - 1355-0284
DOI - 10.1007/s13365-021-00970-4
Subject(s) - methamphetamine , neurocognitive , meth , nitric oxide , peroxynitrite , neurotoxicity , oxidative stress , citric acid cycle , chemistry , human immunodeficiency virus (hiv) , enzyme , neuroscience , biochemistry , medicine , pharmacology , psychology , cognition , immunology , toxicity , monomer , organic chemistry , acrylate , superoxide , polymer
In the brain, both HIV-1 and methamphetamine (meth) use result in increases in oxidative and nitrosative stress. This redox stress is thought to contribute to the pathogenesis of HIV-associated neurocognitive disorder (HAND) and further worsening cognitive activity in the setting of drug abuse. One consequence of such redox stress is aberrant protein S-nitrosylation, derived from nitric oxide, which may disrupt normal protein activity. Here, we report an improved, mass spectrometry-based technique to assess S-nitrosylated protein in human postmortem brains using selective enrichment of S-nitrosocysteine residues with an organomercury resin. The data show increasing S-nitrosylation of tricarboxylic acid (TCA) enzymes in the setting of HAND and HAND/meth use compared with HIV+ control brains without CNS pathology. The consequence is systematic inhibition of multiple TCA cycle enzymes, resulting in energy collapse that can contribute to the neuronal and synaptic damage observed in HAND and meth use.