{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T13:59:08Z","timestamp":1793109548303,"version":"4.5.0"},"reference-count":128,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T00:00:00Z","timestamp":1655424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["R01 DA039789"],"award-info":[{"award-number":["R01 DA039789"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>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 1\u03b1 (IRE1\u03b1) was most prominently upregulated following both HIV-1 infection and chronic METH exposure. Moreover, pharmacological inhibition of the three UPR arms highlighted IRE1\u03b1 as a key regulator of astrocyte metabolic function. To further explore the regulatory role of astrocyte IRE1\u03b1, astrocytes were transfected with an IRE1\u03b1 overexpression vector followed by activation with the proinflammatory cytokine interleukin 1\u03b2. Overall, our findings confirm IRE1\u03b1 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 IRE1\u03b1. Thus, additional studies are needed to determine how to best balance astrocyte IRE1\u03b1 functions to both promote astrocyte neuroprotective properties while preventing neurotoxic properties during CNS pathologies.<\/jats:p>","DOI":"10.3389\/fnins.2022.906651","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T06:37:43Z","timestamp":1655447863000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["A Non-Canonical Role for IRE1\u03b1 Links ER and Mitochondria as Key Regulators of Astrocyte Dysfunction: Implications in Methamphetamine use and HIV-Associated Neurocognitive Disorders"],"prefix":"10.3389","volume":"16","author":[{"given":"Jessica","family":"Proulx","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satomi","family":"Stacy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In-Woo","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Borgmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e00705","DOI":"10.1128\/mBio.00705-15","article-title":"The endoplasmic reticulum stress sensor inositol-requiring enzyme 1alpha augments bacterial killing through sustained oxidant production.","volume":"6","author":"Abuaita","year":"2015","journal-title":"mBio"},{"key":"B2","doi-asserted-by":"crossref","first-page":"625.e5","DOI":"10.1016\/j.chom.2018.10.005","article-title":"Mitochondria-derived vesicles deliver antimicrobial reactive oxygen species to control phagosome-localized Staphylococcus aureus.","volume":"24","author":"Abuaita","year":"2018","journal-title":"Cell Host Microbe"},{"key":"B3","doi-asserted-by":"publisher","first-page":"210","DOI":"10.4049\/jimmunol.2001321","article-title":"The IRE1alpha stress signaling axis is a key regulator of neutrophil antimicrobial effector function.","volume":"207","author":"Abuaita","year":"2021","journal-title":"J. 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