Advertisement

 

 

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

Beyond the polymerase-γ theory: Production of ROS as a mode of NRTI-induced mitochondrial toxicity.
Author Information (click to view)

Smith RL, Tan JME, Jonker MJ, Jongejan A, Buissink T, Veldhuijzen S, van Kampen AHC, Brul S, van der Spek H,


Smith RL, Tan JME, Jonker MJ, Jongejan A, Buissink T, Veldhuijzen S, van Kampen AHC, Brul S, van der Spek H, (click to view)

Smith RL, Tan JME, Jonker MJ, Jongejan A, Buissink T, Veldhuijzen S, van Kampen AHC, Brul S, van der Spek H,

Advertisement

PloS one 2017 11 0212(11) e0187424 doi 10.1371/journal.pone.0187424

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.

Submit a Comment

Your email address will not be published. Required fields are marked *

4 × 3 =

[ HIDE/SHOW ]