HIV-Tat and Cocaine Impact Brain Energy Metabolism: Redox Modification and Mitochondrial Biogenesis Influence NRF Transc
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HIV-Tat and Cocaine Impact Brain Energy Metabolism: Redox Modification and Mitochondrial Biogenesis Influence NRF Transcription-Mediated Neurodegeneration Kalaiselvi Sivalingam 1 & Thomas J. Cirino 2 & Jay P. McLaughlin 2 & Thangavel Samikkannu 1 Received: 10 July 2020 / Accepted: 14 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract HIV infection and drugs of abuse induce oxidative stress and redox imbalance, which cause neurodegeneration. The mechanisms by which HIV infection and cocaine consumption affect astrocyte energy metabolism, and how this leads to neurodegenerative dysfunction, remain poorly understood. Presently, we investigated how oxidative injury causes the depletion of energy resources and glutathione synthetase (GSS), which in turn activates 5’ AMP-activated protein kinase (AMPK), glycolytic enzymes, and mitochondrial biogenesis, finally resulting in nuclear factor erythroid (NRF) transcription in astrocytes. Both human primary astrocytes incubated with HIV-1 Tat protein in vitro and HIV-inducible Tat (iTat) mice exposed to cocaine showed decreased levels of GSS and increased superoxide dismutase (SOD) levels. These changes, in turn, significantly activated AMPK and raised the concentrations of several glycolytic enzymes, along with oxidative phosphorylation, the mitochondrial biogenesis of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) and mitochondrial transcription factor (TFAM), and Nrf1 and Nrf2 gene transcription and protein expression. Moreover, neurons exposed to HIV-1Tat/cocaine-conditioned media showed reductions in dendritic formation, spine density, and neuroplasticity compared with control neurons. These results suggest that redox inhibition of GSS altered AMPK activation and mitochondrial biogenesis to influence Nrf transcription. These processes are important components of the astrocyte signaling network regulating brain energy metabolism in HIV-positive cocaine users. In conclusion, HIV-1 Tat alters redox inhibition, thus increasing glycolytic metabolic profiles and mitochondrial biogenesis, leading to Nrf transcription, and ultimately impacting astrocyte energy resource and metabolism. Cocaine exacerbated these effects, leading to a worsening of neurodegeneration. Keywords HIV-1 Tat . Cocaine . Oxidative stress . Energy deficits . Mitochondria . Astrocytes
Abbreviations iTat HIV-1 inducible Tat (transgenic mice) HIV-1 Tat Transactivator protein ROS Reactive oxygen species GFAP Glial acidic fibril protein GSS Glutathione synthetase CAT Catalase
SOD HAND AMPK HK ACC PFK LDHA MCT PGC1α
* Thangavel Samikkannu [email protected]
TFAM CaMK CREB ACC OXPHOS NRF ARE
1
Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, 1010 W Avenue B, Kingsville, TX 78363, USA
2
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA
Super oxide dismutase HIV-associated neurocognitive disorders 5′ AMP-activated protein kinase Hexo kinase Acety
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