title: Caenorhabditis elegans as a Model System for Studying Drug Induced Mitochondrial Toxicity.
abstract: 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.
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: de Boer
authors.affiliation: 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.
authors.forename: Ruben L
authors.initials: RL
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Winnok H
authors.initials: WH
authors.lastname: De Vos
authors.affiliation: van Leeuwenhoek Center for Advanced Microscopy, Swammerdam Institute for Life Sciences (SILS), Faculty of Science (FNWI), University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands.
authors.forename: Erik M M
authors.initials: EM
authors.lastname: Manders
authors.affiliation: 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.
authors.forename: Stanley
authors.initials: S
authors.lastname: Brul
authors.affiliation: 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.
authors.forename: Hans
authors.initials: H
authors.lastname: van der Spek
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D016049:Didanosine / Q000633:toxicity; D015224:Dideoxynucleosides / Q000633:toxicity; D004341:Drug Evaluation / Q000379:methods*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D010101:Oxygen Consumption / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*; D018119:Stavudine / Q000633:toxicity; D014451:Ubiquinone / Q000037:antagonists & inhibitors / Q000378:metabolism; D016047:Zalcitabine / Q000633:toxicity; D015215:Zidovudine / Q000633:toxicity
chemical_list: D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D015224:Dideoxynucleosides; D024101:Mitochondrial Proteins; D018894:Reverse Transcriptase Inhibitors; D014451:Ubiquinone; D015215:Zidovudine; D016047:Zalcitabine; D018119:Stavudine; D004259:DNA-Directed DNA Polymerase; D016049:Didanosine; C030571:ubiquinone 9; C002854:alovudine