HIV-1 gp120-Induced Endolysosome de-Acidification Leads to Efflux of Endolysosome Iron, and Increases in Mitochondrial Iron and Reactive Oxygen Species.
HIV-1 gp120-Induced Endolysosome de-Acidification Leads to Efflux of Endolysosome Iron, and Increases in Mitochondrial Iron and Reactive Oxygen Species.
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DOI：
10.1007/s11481-021-09995-2
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发表时间：
2022-06
期刊：
影响因子：
--
通讯作者：
Geiger JD
中科院分区：
文献类型：
--
作者：
Halcrow PW;Lakpa KL;Khan N;Afghah Z;Miller N;Datta G;Chen X;Geiger JD
HIV-1外壳蛋白gp120继续参与HIV-1相关神经认知障碍（HAND）的发病机制；已知约50%的HIV-1感染者（PLWH）患有此病。尸检HAND个体的脑组织显示线粒体和内溶酶体的形态学改变，HIV-1 gp120导致线粒体功能障碍，包括活性氧（ROS）水平升高和内溶酶体的去酸化。亚铁直接与ROS的产生有关，亚铁包含在内溶酶体中并从内溶酶体释放，PLWH的铁和ROS水平升高。基于这些发现，我们验证了HIV-1 gp120诱导的内溶酶体去酸化和随后内溶酶体的铁外排是导致ROS水平升高的原因。在U87MG胶质母细胞瘤细胞中，HIV-1 gp120去酸化内溶酶体，降低内溶酶体铁水平，增加细胞质和线粒体铁水平，增加细胞质和线粒体ROS水平。这些作用都被内溶酶体特异性铁螯合剂去铁胺、内溶酶体驻留双孔通道和二价金属转运蛋白-1 （DMT-1）抑制剂、线粒体驻留DMT-1和线粒体通透性过渡孔抑制剂显著减弱。这些结果表明，在HIV-1 gp120中常见的氧化应激是其去酸内溶酶体、增加从内溶酶体释放铁和增加铁进入线粒体的能力的下游。因此，内溶酶体可能是HAND治疗策略的早期和上游靶点。
The HIV-1 coat protein gp120 continues to be implicated in the pathogenesis of HIV-1 associated neurocognitive disorder (HAND); a condition known to affect ~50% of people living with HIV-1 (PLWH). Autopsy brain tissues of HAND individuals display morphological changes to mitochondria and endolysosomes, and HIV-1 gp120 causes mitochondrial dysfunction including increased levels of reactive oxygen species (ROS) and de-acidification of endolysosomes. Ferrous iron is linked directly to ROS production, ferrous iron is contained in and released from endolysosomes, and PLWH have elevated iron and ROS levels. Based on those findings, we tested the hypothesis that HIV-1 gp120-induced endolysosome de-acidification and subsequent iron efflux from endolysosomes is responsible for increased levels of ROS. In U87MG glioblastoma cells, HIV-1 gp120 de-acidified endolysosomes, reduced endolysosome iron levels, increased levels of cytosolic and mitochondrial iron, and increased levels of cytosolic and mitochondrial ROS. These effects were all attenuated significantly by the endolysosome-specific iron chelator deferoxamine, by inhibitors of endolysosome-resident two-pore channels and divalent metal transporter-1 (DMT-1), and by inhibitors of mitochondria-resident DMT-1 and mitochondrial permeability transition pores. These results suggest that oxidative stress commonly observed with HIV-1 gp120 is downstream of its ability to de-acidify endolysosomes, to increase the release of iron from endolysosomes, and to increase the uptake of iron into mitochondria. Thus, endolysosomes might represent early and upstream targets for therapeutic strategies against HAND.
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DOI：
10.1152/ajprenal.00359.2005
发表时间：
2006-06-01
影响因子：
4.2
作者：
Abouhamed, M;Gburek, J;Smith, CP
通讯作者：
Smith, CP
影响因子：
3.2
作者：
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影响因子：
64.5
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通讯作者：
Stockwell BR
影响因子：
16.6
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Xu, Haoxing
DOI：
10.1083/jcb.201602069
发表时间：
2016-09-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Das A;Nag S;Mason AB;Barroso MM
通讯作者：
Barroso MM