HIV and Cocaine Impact Glial Metabolism: Energy Sensor AMP-activated protein kinase Role in Mitochondrial Biogenesis and Epigenetic Remodeling.

Thangavel Samikkannu,Venkata S R Atluri,Madhavan P N Nair

doi:10.1038/srep31784

Thangavel Samikkannu, Venkata S R Atluri + Show 1 more

Open Access

https://doi.org/10.1038/srep31784

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Journal: Scientific Reports	Publication Date: Aug 18, 2016
Citations: 27	License type: CC BY 4.0

Affiliation: Florida International University

Abstract

HIV infection and cocaine use have been identified as risk factors for triggering neuronal dysfunction. In the central nervous system (CNS), energy resource and metabolic function are regulated by astroglia. Glia is the major reservoir of HIV infection and disease progression in CNS. However, the role of cocaine in accelerating HIV associated energy deficit and its impact on neuronal dysfunction has not been elucidated yet. The aim of this study is to elucidate the molecular mechanism of HIV associated neuropathogenesis in cocaine abuse and how it accelerates the energy sensor AMPKs and its subsequent effect on mitochondrial oxidative phosphorylation (OXPHOS), BRSKs, CDC25B/C, MAP/Tau, Wee1 and epigenetics remodeling complex SWI/SNF. Results showed that cocaine exposure during HIV infection significantly increased the level of p24, reactive oxygen species (ROS), ATP-utilization and upregulated energy sensor AMPKs, CDC25B/C, MAP/Tau and Wee1 protein expression. Increased ROS production subsequently inhibits OCR/ECAR ratio and OXPHOS, and eventually upregulate epigenetics remodeling complex SWI/SNF in CHME-5 cells. These results suggest that HIV infection induced energy deficit and metabolic dysfunction is accelerated by cocaine inducing energy sensor AMPKs, mitochondrial biogenesis and chromatin remodeling complex SWI/SNF activation, which may lead to neuroAIDS disease progression.

Highlights

Energy source of intracellular ATP depletion known to threaten cellular homeostasis and integrity
Studies have shown that HIV positive subjects who have used illicit drugs are more sensitive to neuropathogenesis than either substance abusers or HIV infection alone[5,6,34]
We studied these interactions in the downstream signaling intermediate in acetyl-coA carboxylase (ACC), CDC25B/C, microtubule-associated proteins (MAP)/Tau, Wee[1] and oxidative damage of mitochondrial biogenesis, and SWI/ SNF lead neuropathogenesis in CHME-5 cells

Summary

Introduction

Energy source of intracellular ATP depletion known to threaten cellular homeostasis and integrity. NUAK2 is called SNF1/AMPK-related kinase (SNARK) and this SNF1 is the yeast homologue of AMPK, which is a key regulator of cellular energy homeostasis and play a major role in switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. This SNF1/SWI complex contains either ATPase Brm or Brg[1] and Bmi-1, and all of them play important role in neural development[18,25] as well as HIV infection and disease progression[26]. The role of energy sensor AMPKs mediated activation of BRSKs and SNARK proteins leading to metabolic deficit have not been studied yet with respect to the combine effect of cocaine and HIV infection. We highlight the role of energy sensor AMPKs and mitochondrial biogenesis with subsequent impact of epigenetic remodeling on the complex SWI/SNF which may have potential role in progression to neuroAIDS

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