Endolysosome Iron Chelation Inhibits HIV-1 Protein-Induced Endolysosome De-Acidification-Induced Increases in Mitochondrial Fragmentation, Mitophagy, and Cell Death.
Endolysosome Iron Chelation Inhibits HIV-1 Protein-Induced Endolysosome De-Acidification-Induced Increases in Mitochondrial Fragmentation, Mitophagy, and Cell Death.
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作者：
人类免疫缺陷病毒 1 (PLWH) 感染者出现 HIV-1 相关神经认知障碍 (HAND) 的几率很高；临床症状范围从无症状到出现艾滋病毒相关痴呆。抗逆转录病毒治疗有效延长了感染者的预期寿命；然而，手部疾病的患病率有所增加。与 HAND 发病机制有关的是两种 HIV-1 蛋白：转录反式激活蛋白 (Tat) 和 gp120；两者都具有神经毒性并损害线粒体。当活性氧 (ROS) 水平增加时，功能性线粒体的线状形态特征会变得支离破碎，并且在亚铁 (Fe2+) 存在的情况下，可以通过类芬顿化学产生 ROS。内溶酶体是细胞内铁运输的核心，含有易于释放的 Fe2+ 储备。然而，尚不清楚内溶酶体储存是否足以解释损伤诱导的 ROS 水平增加、线粒体碎片、自噬和细胞死亡。使用U87MG星形细胞瘤和SH-SY5Y神经母细胞瘤细胞，我们确定氯喹（CQ）、Tat和gp120均（1）使内溶酶体脱酸，（2）减少内溶酶体数量并增加内溶酶体大小，（3）增加线粒体数量（碎片），（4）增加自噬体数量，（5）增加自噬溶酶体数量，（6）增加内溶酶体数量内溶酶体，(7) 增加细胞死亡。这些作用均被内溶酶体特异性铁螯合剂去铁胺 (DFO) 阻断。因此，内溶酶体脱酸诱导的内溶酶体 Fe2+ 释放足以解释细胞器间信号传导事件和 HIV-1 蛋白的细胞生物学后果，包括线粒体断裂、自噬和细胞死亡。
People with human immunodeficiency virus-1 (PLWH) experience high rates of HIV-1-associated neurocognitive disorders (HANDs); clinical symptoms range from being asymptomatic to experiencing HIV-associated dementia. Antiretroviral therapies have effectively prolonged the life expectancy related to PLWH; however, the prevalence of HANDs has increased. Implicated in the pathogenesis of HANDs are two HIV-1 proteins, transactivator of transcription (Tat) and gp120; both are neurotoxic and damage mitochondria. The thread-like morphological features of functional mitochondria become fragmented when levels of reactive oxygen species (ROS) increase, and ROS can be generated via Fenton-like chemistry in the presence of ferrous iron (Fe2+). Endolysosomes are central to iron trafficking in cells and contain readily releasable Fe2+ stores. However, it is unclear whether the endolysosome store is sufficient to account for insult-induced increases in levels of ROS, mitochondrial fragmentation, autophagy, and cell death. Using U87MG astrocytoma and SH-SY5Y neuroblastoma cells, we determined that chloroquine (CQ), Tat, and gp120 all (1) de-acidified endolysosomes, (2) decreased endolysosome numbers and increased endolysosome sizes, (3) increased mitochondrial numbers (fragmentation), (4) increased autophagosome numbers, (5) increased autolysosome numbers, (6) increased mitochondrial fragments within endolysosomes, and (7) increased cell death. These effects were all blocked by the endolysosome-specific iron chelator deferoxamine (DFO). Thus, the endolysosome de-acidification-induced release of endolysosome Fe2+ is sufficient to account for inter-organellar signaling events and cell biology consequences of HIV-1 proteins, including mitochondrial fragmentation, autophagy, and cell death.
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DOI：
10.1007/s11481-021-09995-2
发表时间：
2022-06
期刊：
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
影响因子：
--
作者：
Halcrow PW;Lakpa KL;Khan N;Afghah Z;Miller N;Datta G;Chen X;Geiger JD
通讯作者：
Geiger JD
影响因子：
11.4
作者：
El-Amine R;Germini D;Zakharova VV;Tsfasman T;Sheval EV;Louzada RAN;Dupuy C;Bilhou-Nabera C;Hamade A;Najjar F;Oksenhendler E;Lipinski M;Chernyak BV;Vassetzky YS
通讯作者：
Vassetzky YS
影响因子：
2.6
作者：
Kasala S;Briyal S;Prazad P;Ranjan AK;Stefanov G;Donovan R;Gulati A
通讯作者：
Gulati A
影响因子：
4.7
作者：
通讯作者：
--
影响因子：
4.8
作者：
Ali, Ibraheem;Ramage, Holly;Ott, Melanie
通讯作者：
Ott, Melanie