{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:50:13Z","timestamp":1788922213755,"version":"build-2803163510"},"reference-count":82,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute on Drug Abuse","award":["R00DA039791"],"award-info":[{"award-number":["R00DA039791"]}]},{"name":"National Institute on Drug Abuse","award":["R01DA052851"],"award-info":[{"award-number":["R01DA052851"]}]},{"name":"The University of Mississippi School of Pharmacy","award":["R00DA039791"],"award-info":[{"award-number":["R00DA039791"]}]},{"name":"The University of Mississippi School of Pharmacy","award":["R01DA052851"],"award-info":[{"award-number":["R01DA052851"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>HIV-associated neurocognitive disorders are prevalent despite antiretroviral intervention. Some HIV virotoxins, such as the trans-activator of transcription (Tat), are not targeted by antiretrovirals, and their neurotoxic actions may be exacerbated by opioids. Both Tat and morphine disrupt mitochondrial function, which may promote neurotoxicity, but the mechanisms are poorly understood. Herein, we assess the capacity of HIV Tat and morphine to alter the fundamental ability of mitochondria to generate and transfer energy along the electron transport chain (ETC). We find that exposure to Tat inhibits mitochondrial respiration driven by ETC complexes I or II in a concentration-dependent manner. Findings were consistent across models of permeabilized neuroblastoma cells, murine-derived mitoplasts, and mitochondria derived from mice exposed to Tat in vivo. In cell culture models, Tat promoted Ca2+ influx and the generation of cytosolic reactive oxygen species (ROS). Acute exposure to morphine exerted no effect on mitochondrial respiration, but morphine modestly offset Tat-mediated effects on complex I and some effects for the generation of ROS. Morphine did not exert any protective effects when acutely administered in vivo. The mitoprotective steroid, allopregnanolone (AlloP), increased mitochondrial respiration in neuroblastoma cells (complex I) or mitoplasts (complex II) and attenuated Tat-mediated impairment of complexes I and II in neuroblastoma cells or mice exposed to Tat in vivo. AlloP further attenuated Tat-mediated intracellular Ca2+ influx and cytosolic ROS production. Taken together, these results suggest that HIV Tat compromises mitochondrial function through the impairment of respiratory complexes I and II and that physiological AlloP may exert protective effects.<\/jats:p>","DOI":"10.3390\/antiox14040420","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T11:17:57Z","timestamp":1743506277000},"page":"420","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["HIV-1 Tat Impairment of Mitochondrial Respiration via Complexes I and II Can Be Ameliorated by Allopregnanolone in Opioid-Exposed or Opioid-Na\u00efve Cells and Mice"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4891-2992","authenticated-orcid":false,"given":"Fakhri","family":"Mahdi","sequence":"first","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zia","family":"Shariat-Madar","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA"},{"name":"Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677-1848, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5628-1134","authenticated-orcid":false,"given":"Jason J.","family":"Paris","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA"},{"name":"Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677-1848, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nrneurol.2016.27","article-title":"HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment","volume":"12","author":"Saylor","year":"2016","journal-title":"Nat. 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