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Mitochondrial Dysfunction Confers Resistance to Multiple Drugs in Caenorhabditis elegans

In a previous genetic screen for Caenorhabditis elegans mutants that survive in the presence of an antimitotic drug, hemiasterlin, we identified eight strong mutants. Two of these were found to be resistant to multiple toxins, and in one of these we identified a missense mutation in phb-2, which enc...

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Autores principales: Zubovych, Iryna O., Straud, Sarah, Roth, Michael G.
Formato: Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836976/
https://www.ncbi.nlm.nih.gov/pubmed/20089839
http://dx.doi.org/10.1091/mbc.E09-08-0673
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author Zubovych, Iryna O.
Straud, Sarah
Roth, Michael G.
author_facet Zubovych, Iryna O.
Straud, Sarah
Roth, Michael G.
author_sort Zubovych, Iryna O.
collection PubMed
description In a previous genetic screen for Caenorhabditis elegans mutants that survive in the presence of an antimitotic drug, hemiasterlin, we identified eight strong mutants. Two of these were found to be resistant to multiple toxins, and in one of these we identified a missense mutation in phb-2, which encodes the mitochondrial protein prohibitin 2. Here we identify two additional mutations that confer drug resistance, spg-7 and har-1, also in genes encoding mitochondrial proteins. Other mitochondrial mutants, isp-1, eat-3, and clk-1, were also found to be drug-resistant. Respiratory complex inhibitors, FCCP and oligomycin, and a producer of reactive oxygen species (ROS), paraquat, all rescued wild-type worms from hemiasterlin toxicity. Worms lacking mitochondrial superoxide dismutase (MnSOD) were modestly drug-resistant, and elimination of MnSOD in the phb-2, har-1, and spg-7 mutants enhanced resistance. The antioxidant N-acetyl-l-cysteine prevented mitochondrial inhibitors from rescuing wild-type worms from hemiasterlin and sensitized mutants to the toxin, suggesting that a mechanism sensitive to ROS is necessary to trigger drug resistance in C. elegans. Using genetics, we show that this drug resistance requires pkc-1, the C. elegans ortholog of human PKCε.
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spelling pubmed-28369762010-05-30 Mitochondrial Dysfunction Confers Resistance to Multiple Drugs in Caenorhabditis elegans Zubovych, Iryna O. Straud, Sarah Roth, Michael G. Mol Biol Cell Articles In a previous genetic screen for Caenorhabditis elegans mutants that survive in the presence of an antimitotic drug, hemiasterlin, we identified eight strong mutants. Two of these were found to be resistant to multiple toxins, and in one of these we identified a missense mutation in phb-2, which encodes the mitochondrial protein prohibitin 2. Here we identify two additional mutations that confer drug resistance, spg-7 and har-1, also in genes encoding mitochondrial proteins. Other mitochondrial mutants, isp-1, eat-3, and clk-1, were also found to be drug-resistant. Respiratory complex inhibitors, FCCP and oligomycin, and a producer of reactive oxygen species (ROS), paraquat, all rescued wild-type worms from hemiasterlin toxicity. Worms lacking mitochondrial superoxide dismutase (MnSOD) were modestly drug-resistant, and elimination of MnSOD in the phb-2, har-1, and spg-7 mutants enhanced resistance. The antioxidant N-acetyl-l-cysteine prevented mitochondrial inhibitors from rescuing wild-type worms from hemiasterlin and sensitized mutants to the toxin, suggesting that a mechanism sensitive to ROS is necessary to trigger drug resistance in C. elegans. Using genetics, we show that this drug resistance requires pkc-1, the C. elegans ortholog of human PKCε. The American Society for Cell Biology 2010-03-15 /pmc/articles/PMC2836976/ /pubmed/20089839 http://dx.doi.org/10.1091/mbc.E09-08-0673 Text en © 2010 by The American Society for Cell Biology
spellingShingle Articles
Zubovych, Iryna O.
Straud, Sarah
Roth, Michael G.
Mitochondrial Dysfunction Confers Resistance to Multiple Drugs in Caenorhabditis elegans
title Mitochondrial Dysfunction Confers Resistance to Multiple Drugs in Caenorhabditis elegans
title_full Mitochondrial Dysfunction Confers Resistance to Multiple Drugs in Caenorhabditis elegans
title_fullStr Mitochondrial Dysfunction Confers Resistance to Multiple Drugs in Caenorhabditis elegans
title_full_unstemmed Mitochondrial Dysfunction Confers Resistance to Multiple Drugs in Caenorhabditis elegans
title_short Mitochondrial Dysfunction Confers Resistance to Multiple Drugs in Caenorhabditis elegans
title_sort mitochondrial dysfunction confers resistance to multiple drugs in caenorhabditis elegans
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836976/
https://www.ncbi.nlm.nih.gov/pubmed/20089839
http://dx.doi.org/10.1091/mbc.E09-08-0673
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