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Caenorhabditis elegans as a Model System for Studying Drug Induced Mitochondrial Toxicity.

de Boer R, Smith RL, De Vos WH, Manders EM, Brul S, van der Spek H - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Oxygen consumption rates in NRTI exposed worms.Drug concentration was 100μM in all experiments. FLT and AZT exposed worms show a significantly reduced oxygen consumption rate compared to unexposed animals. C = Control, ** p-value <0.01, *** p-value <0.001. Significance was determined using a two tailed student’s t-test assuming unequal variance.
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pone.0126220.g003: Oxygen consumption rates in NRTI exposed worms.Drug concentration was 100μM in all experiments. FLT and AZT exposed worms show a significantly reduced oxygen consumption rate compared to unexposed animals. C = Control, ** p-value <0.01, *** p-value <0.001. Significance was determined using a two tailed student’s t-test assuming unequal variance.

Mentions: Whereas FLT and AZT induce a significant reduction of oxygen consumption, no significant effects were observed after treatment with d4T, ddC or ddI (Fig 3). For d4T, ddC and ddI these results correlate well with the lack of mtDNA depletion seen with these NRTIs at this concentration and incubation time (Table 1). In the case of AZT treated worms however, a significant decrease in oxygen consumption can be observed despite the absence of mtDNA depletion with this NRTI (Table 1).


Caenorhabditis elegans as a Model System for Studying Drug Induced Mitochondrial Toxicity.

de Boer R, Smith RL, De Vos WH, Manders EM, Brul S, van der Spek H - PLoS ONE (2015)

Oxygen consumption rates in NRTI exposed worms.Drug concentration was 100μM in all experiments. FLT and AZT exposed worms show a significantly reduced oxygen consumption rate compared to unexposed animals. C = Control, ** p-value <0.01, *** p-value <0.001. Significance was determined using a two tailed student’s t-test assuming unequal variance.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430419&req=5

pone.0126220.g003: Oxygen consumption rates in NRTI exposed worms.Drug concentration was 100μM in all experiments. FLT and AZT exposed worms show a significantly reduced oxygen consumption rate compared to unexposed animals. C = Control, ** p-value <0.01, *** p-value <0.001. Significance was determined using a two tailed student’s t-test assuming unequal variance.
Mentions: Whereas FLT and AZT induce a significant reduction of oxygen consumption, no significant effects were observed after treatment with d4T, ddC or ddI (Fig 3). For d4T, ddC and ddI these results correlate well with the lack of mtDNA depletion seen with these NRTIs at this concentration and incubation time (Table 1). In the case of AZT treated worms however, a significant decrease in oxygen consumption can be observed despite the absence of mtDNA depletion with this NRTI (Table 1).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus