Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
Department of Medical Genetics and Molecular Biochemistry and the Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
Cell Death Dis. 2018 Apr 1;9(4):415. doi: 10.1038/s41419-018-0422-3.
Calcium (Ca) dynamics and oxidative signaling control mitochondrial bioenergetics in the central nervous system, where astrocytes are a major energy source for neurons. Cocaine use exacerbates HIV-associated neurocognitive disorders, but little is known about disruptions in astrocyte metabolism in this context. Our data show that the HIV protein Tat and cocaine induce a metabolic switch from glucose to fatty acid oxidation in astrocytes, thereby limiting lactate transport to neurons. Mechanistic analyses revealed increased Mitochondrial Ca Uniporter (MCU)-mediated Ca uptake in astrocytes exposed to Tat and cocaine due to oxidation of MCU. Since our data suggest that mitochondrial oxidation is dependent in part on MCU-mediated Ca uptake, we targeted MCU to restore glycolysis in astrocytes to normalize extracellular lactate levels. Knocking down MCU in astrocytes prior to Tat and cocaine exposure prevented metabolic switching and protected neurons. These findings identify a novel molecular mechanism underlying neuropathogenesis in HIV and cocaine use.
钙（Ca）动力学和氧化信号控制中枢神经系统中线粒体的生物能量学，星形胶质细胞是神经元的主要能量来源。可卡因的使用会加剧与 HIV 相关的神经认知障碍，但在此背景下，星形胶质细胞代谢紊乱的情况知之甚少。我们的数据表明，HIV 蛋白 Tat 和可卡因诱导星形胶质细胞从葡萄糖代谢向脂肪酸氧化的代谢转换，从而限制了乳酸向神经元的转运。机制分析表明，由于 MCU 的氧化，暴露于 Tat 和可卡因的星形胶质细胞中线粒体钙单向转运体（MCU）介导的 Ca 摄取增加。由于我们的数据表明线粒体氧化部分依赖于 MCU 介导的 Ca 摄取，因此我们针对 MCU 以恢复星形胶质细胞中的糖酵解，使细胞外乳酸水平正常化。在 Tat 和可卡因暴露之前敲低星形胶质细胞中的 MCU 可防止代谢转换并保护神经元。这些发现确定了 HIV 和可卡因使用导致神经病变的新的分子机制。
