Methamphetamine Augments Concurrent Astrocyte Mitochondrial Stress, Oxidative Burden, and Antioxidant Capacity: Tipping the Balance in HIV-Associated Neurodegeneration.
Methamphetamine Augments Concurrent Astrocyte Mitochondrial Stress, Oxidative Burden, and Antioxidant Capacity: Tipping the Balance in HIV-Associated Neurodegeneration.
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DOI：
10.1007/s12640-017-9812-z
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发表时间：
2018-03
影响因子：
3.7
通讯作者：
Ghorpade A
中科院分区：
文献类型：
--
作者：
Borgmann K;Ghorpade A
甲基苯丙胺（METH）的使用，与和不与人类免疫缺陷病毒（HIV）-1合并症，加剧神经认知能力下降。氧化应激是HIV-1中枢神经系统感染和METH滥用期间的一种可能的神经毒性机制;作为病毒蛋白，抗逆转录病毒治疗和METH均已被证明可诱导线粒体功能障碍。然而，在HIV-1感染和METH滥用的背景下，调节星形胶质细胞中线粒体稳态和总体氧化负荷的机制还没有得到很好的理解。在这里，我们报告了在长时间暴露于低水平的METH时，METH介导的星形胶质细胞线粒体形态和功能失调。当通过机器学习、分割分析进行评估时，线粒体变得更大，并且METH更呈杆状。这些变化可能介导的线粒体融合蛋白的表达升高加上抑制磷酸化的动力蛋白相关蛋白-1，调节线粒体融合和分裂，分别。虽然在急性暴露期间METH降低了氧消耗和ATP水平，但在没有METH的情况下进行测试时，一到两周的慢性治疗显着增强了两者。总之，这些变化显着增加抗氧化蛋白的表达，增强星形胶质细胞的氧化能力，但也氧化损伤。我们认为，靶向星形胶质细胞以减少其整体氧化负荷并扩大其抗氧化能力，最终可能会使神经毒性的平衡转向神经保护。
Methamphetamine (METH) use, with and without human immunodeficiency virus (HIV)-1 comorbidity, exacerbates neurocognitive decline. Oxidative stress is a probable neurotoxic mechanism during HIV-1 central nervous system infection and METH abuse; as viral proteins, antiretroviral therapy and METH have each been shown to induce mitochondrial dysfunction. However, the mechanisms regulating mitochondrial homeostasis and overall oxidative burden in astrocytes are not well understood in the context of HIV-1 infection and METH abuse. Here we report METH-mediated dysregulation of astrocyte mitochondrial morphology and function during prolonged exposure to low levels of METH. Mitochondria became larger and more rod shaped with METH when assessed by machine learning, segmentation analyses. These changes may be mediated by elevated mitofusin expression coupled with inhibitory phosphorylation of dynamin-related protein-1, which regulate mitochondrial fusion and fission, respectively. While METH decreased oxygen consumption and ATP levels during acute exposure, chronic treatment of one to two weeks significantly enhanced both when tested in the absence of METH. Together, these changes significantly increased expression of antioxidant proteins, augmenting the astrocyte’s oxidative capacity, but also oxidative damage. We propose that targeting astrocytes to reduce their overall oxidative burden and expand their antioxidant capacity could ultimately tip the balance from neurotoxicity towards neuroprotection.
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