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| Status |
Public on Feb 13, 2018 |
| Title |
Beyond the polymerase-gamma theory: Respiratory chain inhibition and production of ROS as modes of NRTI induced mitochondrial toxicity |
| Organism |
Caenorhabditis elegans |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
HIV-1 nucleoside reverse transcriptase inhibitor (NRTI) use is associated with severe adverse events. However, the exact mechanisms behind their toxicity has not been fully understood. Mitochondrial dysfunction after chronic exposure to NRTIs has predominantly been assigned to mitochondrial polymerase- 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 these drugs, which are rarely discussed in the literature, include direct inhibition of the mitochondrial respiratory chain (MRC), 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.
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| Overall design |
RNA-seq on Caenorhabditis elegans exposed to DMSO, 3'-azido-3'-deoxythymidine (zidovudine or AZT), 2',3'-didehydro-2',3'-deoxythymidine (stavudine or d4T), 3'-deoxy-3'-fluorothymidine (alovudine or FLT) or untreated control after 24 or 72 hours of exposure.
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| Contributor(s) |
Smith RL, Tan JM, Jonker MJ, Jongejan A, Buissink T, Veldhuijzen S, van Kampen AH, Brul S, van der Spek H |
| Citation(s) |
29095935 |
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| Submission date |
Jun 26, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Martijs Jonker |
| E-mail(s) |
m.j.jonker@uva.nl
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| Organization name |
University of Amsterdam
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| Department |
Microarray Department
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| Street address |
Science Park 904
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| City |
Amsterdam |
| ZIP/Postal code |
1090 GE |
| Country |
Netherlands |
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| Platforms (1) |
| GPL13657 |
Illumina HiSeq 2000 (Caenorhabditis elegans) |
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| Samples (30)
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| Relations |
| BioProject |
PRJNA391939 |
| SRA |
SRP110515 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE100482_RAW.tar |
4.3 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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