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

R.L. Smith, J.M.E. Tan, M.J. Jonker, A. Jongejan, T. Buissink, S. Veldhuijzen, A.H.C. van Kampen, S. Brul, H. van der Spek

Research output: Contribution to journalArticleAcademicpeer-review

23 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere0187424
Pages (from-to)e0187424
Number of pages23
JournalPLoS ONE
Volume12
Issue number11
DOIs
Publication statusPublished - 2 Nov 2017

Keywords

  • Animals
  • Anti-HIV Agents
  • Caenorhabditis elegans
  • DNA-Directed DNA Polymerase
  • Humans
  • Journal Article
  • Mitochondria
  • Reactive Oxygen Species
  • Reverse Transcriptase Inhibitors

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