HIV and Cocaine Impact Glial Metabolism: Energy Sensor AMP-activated protein kinase Role in Mitochondrial Biogenesis and Epigenetic Remodeling
HIV and Cocaine Impact Glial Metabolism: Energy Sensor AMP-activated protein kinase Role in Mitochondrial Biogenesis and Epigenetic Remodeling
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DOI：
10.1038/srep31784
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发表时间：
2016-08-18
影响因子：
4.6
通讯作者：
Nair, Madhavan P. N.
中科院分区：
文献类型：
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作者：
Samikkannu, Thangavel;Atluri, Venkata S. R.;Nair, Madhavan P. N.
HIV感染和可卡因使用已被确定为引发神经功能障碍的危险因素。在中枢神经系统（CNS）中，能量的来源和代谢功能是由星形胶质细胞调节的。神经胶质细胞是中枢神经系统HIV感染和疾病进展的主要储存库。然而，可卡因在加速HIV相关的能量不足及其对神经元功能障碍的影响中的作用尚未阐明。本研究的目的是阐明可卡因滥用中HIV相关神经发病机制的分子机制，以及它如何加速能量传感器AMPKs及其随后对线粒体氧化磷酸化（OXPHOS）、brsk、CDC25B/C、MAP/Tau、Wee1和表观遗传重塑复合物SWI/SNF的影响。结果表明，在HIV感染期间，可卡因暴露显著增加了p24、活性氧（ROS）、atp利用水平，并上调了能量传感器AMPKs、CDC25B/C、MAP/Tau和Wee1蛋白的表达。增加的ROS产生随后抑制OCR/ECAR比率和OXPHOS，最终上调CHME-5细胞的表观遗传重塑复合体SWI/SNF。这些结果表明，可卡因诱导的能量传感器AMPKs、线粒体生物发生和染色质重塑复合体SWI/SNF激活加速了HIV感染引起的能量不足和代谢功能障碍，这可能导致神经艾滋病疾病的进展。
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.