HIV-Tat and Cocaine Impact Brain Energy Metabolism: Redox Modification and Mitochondrial Biogenesis Influence NRF-Transcriptional Mediated Neurodegeneration
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AbstractHIV infection and drugs of abuse induce oxidative stress and redox imbalance, which cause neurodegeneration. The mechanisms by which HIV infection and cocaine consumption affect astrocytes energy metabolism lead neurodegenerative dysfunction remain poorly understood. We investigated how oxidative injury cause energy resource and depletion of glutathione synthetase (GSS), activating energy sensor AMPK-mediated glycolytic enzymes, and mitochondrial biogenesis lead to NRF transcription factors in astrocytes. Both human primary astrocytes in vitro (HIV-1Tat/cocaine) and HIV-inducible Tat (iTat) mice exposed to cocaine inhibit the GSS and altered superoxide dismutase (SOD) level. This, in turn, significantly activated AMPK and raised the several glycolytic enzymes, oxidative phosphorylation, mitochondrial biogenesis of PGC-1 and TFAM, Nrf1 and Nrf2 gene transcription, and protein expression. These results suggest that redox inhibition of GSS altered AMPK activation and mitochondrial biogenesis influence Nrf transcriptions, which are important resource of astrocytes signaling network in brain energy metabolism in HIV-positive cocaine users. In conclusion, HIV-1 Tat altered redox inhibition, thus raising glycolytic metabolic profiles and mitochondrial biogenesis led to Nrf transcription, which impact astrocyte-energy resource and metabolism. Further cocaine comorbidity exacerbation of these effects led to worse in neurodegeneration.
