de Boer Richard, Smith Ruben L, De Vos Winnok H, Manders Erik M M, Brul Stanley, van der Spek Hans
Molecular Biology & Microbial Food Safety, Swammerdam Institute for Life Sciences (SILS), Faculty of Science (FNWI), University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands.
Cell Biology and Histology Group, Department of Veterinary Sciences, University of Antwerp, Groenenborgerlaan 171, 2020, Antwerp, Belgium; Cell Systems and Imaging Research Group, Department of Molecular Biotechnology, Ghent University, Coupure Links, 653, 9000, Ghent, Belgium.
PLoS One. 2015 May 13;10(5):e0126220. doi: 10.1371/journal.pone.0126220. eCollection 2015.
Today HIV-1 infection is recognized as a chronic disease with obligatory lifelong treatment to keep viral titers below detectable levels. The continuous intake of antiretroviral drugs however, leads to severe and even life-threatening side effects, supposedly by the deleterious impact of nucleoside-analogue type compounds on the functioning of the mitochondrial DNA polymerase. For detailed investigation of the yet partially understood underlying mechanisms, the availability of a versatile model system is crucial. We therefore set out to develop the use of Caenorhabditis elegans to study drug induced mitochondrial toxicity. Using a combination of molecular-biological and functional assays, combined with a quantitative analysis of mitochondrial network morphology, we conclude that anti-retroviral drugs with similar working mechanisms can be classified into distinct groups based on their effects on mitochondrial morphology and biochemistry. Additionally we show that mitochondrial toxicity of antiretroviral drugs cannot be exclusively attributed to interference with the mitochondrial DNA polymerase.
如今，HIV-1感染被视为一种慢性病，需要终身进行强制性治疗以将病毒滴度维持在可检测水平以下。然而，持续服用抗逆转录病毒药物会导致严重甚至危及生命的副作用，据推测这是由于核苷类似物类化合物对线粒体DNA聚合酶功能的有害影响所致。为了详细研究尚未完全了解的潜在机制，拥有一个通用的模型系统至关重要。因此，我们着手开发利用秀丽隐杆线虫来研究药物诱导的线粒体毒性。通过结合分子生物学和功能分析，并对线粒体网络形态进行定量分析，我们得出结论，具有相似作用机制的抗逆转录病毒药物可根据其对线粒体形态和生物化学的影响分为不同类别。此外，我们还表明，抗逆转录病毒药物的线粒体毒性不能完全归因于对线粒体DNA聚合酶的干扰。
