Beyond the polymerase-γ theory: Production of ROS as a mode of NRTI-induced mitochondrial toxicity

• Published in: PloS one Vol. 12; no. 11; p. e0187424
• Main Authors: Smith, Reuben L, Tan, Josephine M E, Jonker, Martijs J, Jongejan, Aldo, Buissink, Thomas, Veldhuijzen, Steve, van Kampen, Antoine H C, Brul, Stanley, van der Spek, Hans
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.11.2017; Public Library of Science (PLoS)
• Subjects: Acetylcysteine; Animals; Anti-HIV Agents - pharmacology; Bioinformatics; Biology and life sciences; Caenorhabditis elegans; Caenorhabditis elegans - drug effects; Chronic exposure; DNA-Directed DNA Polymerase - metabolism; Drug therapy; Enzymes; Epidemiology; Exposure; Fitness; Food safety; Genomes; Humans; Inhibition; Laboratories; Life sciences; Medicine and Health Sciences; Mitochondria; Mitochondria - drug effects; Mitochondrial DNA; Molecular biology; Nematodes; Nucleoside reverse transcriptase inhibitors; Oxidative stress; Oxygen; Oxygen consumption; Reactive oxygen species; Reactive Oxygen Species - metabolism; Research and Analysis Methods; Reverse Transcriptase Inhibitors - poisoning; RNA-directed DNA polymerase; Signaling; Toxicity
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0187424

Use of some HIV-1 nucleoside reverse transcriptase inhibitors (NRTI) is associated with severe adverse events. However, the exact mechanisms behind their toxicity has not been fully understood. Mitochondrial dysfunction after chronic exposure to specific NRTIs has predominantly been assigned to mitochondrial polymerase-γ inhibition by NRTIs. However, an increasing amount of data suggests that this is not the sole mechanism. Many NRTI induced adverse events have been linked to the incurrence of oxidative stress, although the causality of events leading to reactive oxygen species (ROS) production and their role in toxicity is unclear. In this study we show that short-term effects of first generation NRTIs, which are rarely discussed in the literature, include inhibition of oxygen consumption, decreased ATP levels and increased ROS production. Collectively these events affect fitness and longevity of C. elegans through mitohormetic signalling events. Furthermore, we demonstrate that these effects can be normalized by addition of the anti-oxidant N-acetylcysteine (NAC), which suggests that ROS likely influence the onset and severity of adverse events upon drug exposure.