HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-associated neurocognitive disorders
HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-associated neurocognitive disorders
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DOI：
10.1016/j.nbd.2015.11.015
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发表时间：
2016-02-01
影响因子：
6.1
通讯作者：
Masliah, Eliezer
中科院分区：
文献类型：
--
作者：
Fields, Jerel Adam;Serger, Elisabeth;Masliah, Eliezer
HIV相关的神经认知障碍（HAND）仍然发生在大约50%的HIV患者中，迫切需要对抗HAND进展的治疗。HIV蛋白质从受感染的细胞中释放出来，可能通过线粒体异常引起神经元损伤。改变的线粒体（分裂和融合）与几种神经退行性疾病有关。在这里，我们假设线粒体分裂/融合可能是失调的神经元在手。我们已经发现HAND供体的额叶皮质组织中线粒体裂变蛋白（发动蛋白1样; DNM 1 L）减少，并且沿着出现位于受损神经元的索马中的线粒体扩大和延长。在GFAP-gp 120 tg小鼠的脑中观察到类似的病理学。在体外，重组gp 120降低总的和活性DNM 1 L水平，减少Mitotracicer染色的水平，并增加细胞外酸化率（ECAR）在原代神经元。DNM 1 L敲低增强了gp 120的作用，如通过处理的细胞中减少的Mitotracker信号所测量的。有趣的是，DNM 1 L的过表达增加了原代大鼠神经元中Mitotracker染色的水平，并减少了GFAP-gp 120-tg小鼠中的神经炎症和神经变性。这些数据表明，线粒体生物发生动力学在HAND患者的脑中向线粒体融合转移，这可能是由于gp 120诱导的DNM 1 L活性降低。在CNS的HIV感染期间促进线粒体分裂可恢复线粒体生物发生并防止神经变性。(C)2015 Elsevier Inc. All rights reserved.
HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of HIV patients, and therapies to combat HAND progression are urgently needed. HIV proteins are released from infected cells and cause neuronal damage, possibly through mitochondrial abnormalities. Altered mitochondria (fission and fusion is implicated in several neurodegenerative disorders. Here, we hypothesized that mitochondrial fission/fusion may be dysregulated in neurons during HAND. We have identified decreased mitochondrial fission protein (dynamin 1-like; DNM1L) in frontal cortex tissues of HAND donors, along with enlarged and elongated mitochondria localized to the soma of damaged neurons. Similar pathology was observed in the brains of GFAP-gp120 tg mice. In vitro, recombinant gp120 decreased total and active DNM1L levels, reduced the level of Mitotracicer staining, and increased extracellular acidification rate (ECAR) in primary neurons. DNM1L knockdown enhanced the effects of gp120 as measured by reduced Mitotracker signal in the treated cells. Interestingly, overexpression of DNM1L increased the level of Mitotracker staining in primary rat neurons and reduced neuroinflammation and neurodegeneration in the GFAP-gp120-tg mice. These data suggest that mitochondrial biogenesis dynamics are shifted towards mitochondrial fusion in brains of HAND patients and this may be due to gp120-induced reduction in DNM1L activity. Promoting mitochondrial fission during HIV infection of the CNS may restore mitochondrial biogenesis and prevent neurodegeneration. (C) 2015 Elsevier Inc. All rights reserved.