A Non-Canonical Role for IRE1α Links ER and Mitochondria as Key Regulators of Astrocyte Dysfunction: Implications in Methamphetamine use and HIV-Associated Neurocognitive Disorders.
A Non-Canonical Role for IRE1α Links ER and Mitochondria as Key Regulators of Astrocyte Dysfunction: Implications in Methamphetamine use and HIV-Associated Neurocognitive Disorders.
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IRE1α的非经典作用将ER和线粒体作为星形胶质细胞功能障碍的关键调节因子：甲基苯丙胺使用和HIV相关神经认知障碍的影响
DOI：
10.3389/fnins.2022.906651
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发表时间：
2022
影响因子：
4.3
通讯作者：
Borgmann, Kathleen
中科院分区：
文献类型：
--
作者：
Proulx, Jessica;Stacy, Satomi;Park, In-Woo;Borgmann, Kathleen
关键词：
星形胶质细胞是中枢神经系统中数量最多的神经胶质细胞之一，为神经元提供必要的支持，以确保中枢神经系统的健康和功能。在神经病理挑战期间，例如在人类免疫缺陷病毒(HIV)-1感染或(冰毒)苯丙胺暴露期间，星形胶质细胞会改变其神经保护功能，并可能成为神经毒性细胞。识别星形胶质细胞功能障碍的细胞和分子机制对于优化星形胶质细胞和神经元之间的偶联，确保神经元适应中枢神经系统的病理，包括HIV-1相关性神经认知障碍(手)和冰毒使用障碍具有非常重要的意义。线粒体是调节新陈代谢、抗氧化和炎症的重要细胞器。此外，内质网(ER)相关的信号通路，如钙和未折叠蛋白反应(UPR)，是影响细胞命运和功能的重要信使，包括炎症和线粒体动态平衡。越来越多的证据表明，UPR的三个臂通过线粒体相关的内质网膜(MAM)参与内质网和线粒体之间的直接联系和通讯。本研究研究了HIV-1感染和慢性冰毒暴露对星形胶质细胞ER和线粒体稳态的影响，并探讨了这三种UPR信使在星形胶质细胞线粒体功能障碍中的潜在调节作用。原代培养的人星形胶质细胞感染假型HIV-1或低剂量冰毒作用7d后，线粒体耗氧速率(OCR)、胞浆钙流量和UPR介体蛋白表达均增加。值得注意的是，在感染艾滋病毒和慢性冰毒暴露后，肌醇需要蛋白1α(IRE1α)的表达显著上调。此外，对三个UPR臂的药理抑制突出表明IRE1α是星形胶质细胞代谢功能的关键调节因子。为了进一步探讨星形胶质细胞IRE1α的调控作用，将IRE1α过表达载体导入星形胶质细胞，然后用促炎症细胞因子白介素1β激活。总体而言，我们的发现证实了IRE1α调节星形胶质细胞线粒体呼吸、糖酵解功能、形态激活、炎症和谷氨酸摄取，突出了一个调节星形胶质细胞功能障碍的新的潜在靶点。最后，这些发现提示星形胶质细胞IRE1α的典型和非典型UPR机制。因此，需要更多的研究来确定如何最好地平衡星形胶质细胞IRE1α的功能，以促进星形胶质细胞的神经保护特性，同时防止中枢神经系统病理过程中的神经毒性特性。
Astrocytes are one of the most numerous glial cells in the central nervous system (CNS) and provide essential support to neurons to ensure CNS health and function. During a neuropathological challenge, such as during human immunodeficiency virus (HIV)-1 infection or (METH)amphetamine exposure, astrocytes shift their neuroprotective functions and can become neurotoxic. Identifying cellular and molecular mechanisms underlying astrocyte dysfunction are of heightened importance to optimize the coupling between astrocytes and neurons and ensure neuronal fitness against CNS pathology, including HIV-1-associated neurocognitive disorders (HAND) and METH use disorder. Mitochondria are essential organelles for regulating metabolic, antioxidant, and inflammatory profiles. Moreover, endoplasmic reticulum (ER)-associated signaling pathways, such as calcium and the unfolded protein response (UPR), are important messengers for cellular fate and function, including inflammation and mitochondrial homeostasis. Increasing evidence supports that the three arms of the UPR are involved in the direct contact and communication between ER and mitochondria through mitochondria-associated ER membranes (MAMs). The current study investigated the effects of HIV-1 infection and chronic METH exposure on astrocyte ER and mitochondrial homeostasis and then examined the three UPR messengers as potential regulators of astrocyte mitochondrial dysfunction. Using primary human astrocytes infected with pseudotyped HIV-1 or exposed to low doses of METH for 7 days, astrocytes had increased mitochondrial oxygen consumption rate (OCR), cytosolic calcium flux and protein expression of UPR mediators. Notably, inositol-requiring protein 1α (IRE1α) was most prominently upregulated following both HIV-1 infection and chronic METH exposure. Moreover, pharmacological inhibition of the three UPR arms highlighted IRE1α as a key regulator of astrocyte metabolic function. To further explore the regulatory role of astrocyte IRE1α, astrocytes were transfected with an IRE1α overexpression vector followed by activation with the proinflammatory cytokine interleukin 1β. Overall, our findings confirm IRE1α modulates astrocyte mitochondrial respiration, glycolytic function, morphological activation, inflammation, and glutamate uptake, highlighting a novel potential target for regulating astrocyte dysfunction. Finally, these findings suggest both canonical and non-canonical UPR mechanisms of astrocyte IRE1α. Thus, additional studies are needed to determine how to best balance astrocyte IRE1α functions to both promote astrocyte neuroprotective properties while preventing neurotoxic properties during CNS pathologies.
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影响因子：
3.7
作者：
Basova L;Najera JA;Bortell N;Wang D;Moya R;Lindsey A;Semenova S;Ellis RJ;Marcondes MCG
通讯作者：
Marcondes MCG
影响因子：
1
作者：
Cisneros IE;Ghorpade A
通讯作者：
Ghorpade A
影响因子：
11.4
作者：
Area-Gomez, Estela;Castillo, Maria Del Carmen Lara;Tambini, Marc D.;Guardia-Laguarta, Cristina;de Groof, Ad J. C.;Madra, Moneek;Ikenouchi, Junichi;Umeda, Masato;Bird, Thomas D.;Sturley, Stephen L.;Schon, Eric A.
通讯作者：
Schon, Eric A.
影响因子：
5.4
作者：
Canki, M;Thai, JNF;Volsky, DJ
通讯作者：
Volsky, DJ
影响因子：
4.2
作者：
Bettcher BM;Olson KE;Carlson NE;McConnell BV;Boyd T;Adame V;Solano DA;Anton P;Markham N;Thaker AA;Jensen AM;Dallmann EN;Potter H;Coughlan C
通讯作者：
Coughlan C