title: Nucleoside reverse transcriptase inhibitors induce a mitophagy-associated endothelial cytotoxicity that is reversed by coenzyme Q10 cotreatment.
abstract: Cardiovascular complications have been documented in HIV-1 infected populations, and antiretroviral therapy may play a role. Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals known to induce mitochondrial damage in endothelial cells, culminating in endothelial dysfunction, an initiating event in atherogenesis. Though the mechanism for NRTI-induced endothelial toxicity is not yet clear, our prior work suggested that a mitochondrial oxidative stress may be involved. To further delineate the mechanism of toxicity, endothelial cells were treated with NRTIs of varying subclasses, and the level of reactive oxygen species (ROS) and mitochondrial function were assessed. To test whether rescue of mitochondrial electron transport attenuated NRTI-induced endothelial cytotoxicity, in some cases, cells were cotreated with the electron transport cofactor coenzyme Q10 (Q10). At 4-6h, NRTIs increased levels of ROS but decreased the activities of electron transport chain complexes I-IV, levels of ATP and the NAD/NADH ratio. Moreover, nitric oxide levels were decreased, whereas endothelin-1 release was increased. Q10 abolished NRTI-induced mitochondria injury and effects on endothelial agonist production. Interestingly, in cells treated with NRTIs only, markers for mitochondrial toxicity returned to baseline levels by 18-24h, suggesting a compensatory mechanism for clearing damaged mitochondria. Using confocal microscopy, with confirmation utilizing the autophagy and mitophagy markers LC-3 and Nix, respectively, we observed autophagy of mitochondria at 8-10h after treatment. Q10 prevented NRTI-mediated increase in LC-3. These findings suggest that NRTI-induced mitophagy may be involved in NRTI-induced endothelial dysfunction and that this damage likely results from oxidant injury. Further, Q10 supplementation could potentially prevent NRTI-induced endothelial dysfunction.
authors: Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana 71130, USA.
authors: Stephen Y
authors: SY
authors: Xue
authors: Valeria Y
authors: VY
authors: Hebert
authors: Danicia M
authors: DM
authors: Hayes
authors: Corie N
authors: CN
authors: Robinson
authors: Mitzi
authors: M
authors: Glover
authors: Tammy R
authors: TR
authors: Dugas
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004579:Electron Transport / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D063306:Mitophagy / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D017382:Reactive Oxygen Species; D018894:Reverse Transcriptase Inhibitors; D014451:Ubiquinone; D000255:Adenosine Triphosphate; C024989:coenzyme Q10
keywords: antiretrovirals; coenzyme Q10; endothelial dysfunction; mitochondria; mitophagy; nucleoside reverse transcriptase inhibitors; reactive oxygen species
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