Human immunodeficiency virus Tat impairs mitochondrial fission in neurons.
Human immunodeficiency virus Tat impairs mitochondrial fission in neurons.
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DOI：
10.1038/s41420-017-0013-6
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发表时间：
2018-12
影响因子：
7
通讯作者：
Mocchetti I
中科院分区：
文献类型：
--
作者：
Rozzi SJ;Avdoshina V;Fields JA;Mocchetti I
中枢神经系统的人类免疫缺陷病毒 1 (HIV) 感染会促进神经元损伤，最终导致 HIV 相关的神经认知障碍。病毒蛋白，包括转录反式激活蛋白 (Tat)，已成为解释 HIV 介导的神经毒性的主要候选蛋白，但其机制仍不清楚。与对照组相比，Tat 转基因小鼠或暴露于 Tat 的神经元表现出神经元损失，线粒体更小。为了提供关于 Tat 使用哪些机制促进线粒体形态变化的实验线索，将大鼠皮质神经元暴露于 Tat (100nM) 不同时间点。在 30 分钟内，Tat 导致线粒体膜电位显着降低，这一过程受到融合和裂变的调节。为了进一步评估 Tat 是否改变这些过程，分别测量了裂变和融合蛋白动力相关蛋白 1 (Drp1) 和线粒体融合蛋白-2 (Mfn2)。我们发现 Drp1 水平在 Tat 暴露后 2 小时开始增加，而 Mfn2 保持不变。此外，发现接触 Tat 后，Drp1 活性形式的水平增加。此外，Drp1 和钙调神经磷酸酶抑制剂可防止 Tat 介导的对线粒体大小的影响。这些发现表明线粒体裂变可能是 Tat 介导的线粒体形态改变的主要因素。线粒体稳态的破坏可能导致细胞器不稳定，并最终导致 Tat 暴露后神经元细胞死亡。
Human immunodeficiency virus-1 (HIV) infection of the central nervous system promotes neuronal injury that culminates in HIV-associated neurocognitive disorders. Viral proteins, including transactivator of transcription (Tat), have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms remain unclear. Tat transgenic mice or neurons exposed to Tat, which show neuronal loss, exhibit smaller mitochondria as compared to controls. To provide an experimental clue as to which mechanisms are used by Tat to promote changes in mitochondrial morphology, rat cortical neurons were exposed to Tat (100 nM) for various time points. Within 30 min, Tat caused a significant reduction in mitochondrial membrane potential, a process that is regulated by fusion and fission. To further assess whether Tat changes these processes, fission and fusion proteins dynamin-related protein 1 (Drp1) and mitofusin-2 (Mfn2), respectively, were measured. We found that Drp1 levels increased beginning at 2 h after Tat exposure while Mfn2 remained unchanged. Moreover, increased levels of an active form of Drp1 were found to be present following Tat exposure. Furthermore, Drp1 and calcineurin inhibitors prevented Tat-mediated effects on mitochondria size. These findings indicate that mitochondrial fission is likely the leading factor in Tat-mediated alterations to mitochondrial morphology. This disruption in mitochondria homeostasis may contribute to the instability of the organelle and ultimately neuronal cell death following Tat exposure.
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DOI：
10.1038/nrneurol.2014.77
发表时间：
2014-06
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Bennett GJ;Doyle T;Salvemini D
通讯作者：
Salvemini D
DOI：
10.1073/pnas.0611699104
发表时间：
2007-02-27
影响因子：
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作者：
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通讯作者：
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DOI：
10.1006/bbrc.1997.6802
发表时间：
1997-06-18
影响因子：
3.1
作者：
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通讯作者：
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影响因子：
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作者：
Garden, GA;Budd, SL;Lipton, SA
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影响因子：
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作者：
Fields, Jerel Adam;Serger, Elisabeth;Masliah, Eliezer
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