Mitochondrial dysfunction confers resistance to multiple drugs in Caenorhabditis elegans

Iryna O. Zubovych, Sarah Straud, Michael G. Roth

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)956-969
Number of pages14
JournalMolecular Biology of the Cell
Volume21
Issue number6
DOIs
StatePublished - Mar 15 2010

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Caenorhabditis elegans
Multiple Drug Resistance
Drug Resistance
Mitochondrial Proteins
Superoxide Dismutase
Reactive Oxygen Species
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Antimitotic Agents
Oligomycins
Paraquat
Acetylcysteine
Missense Mutation
Pharmaceutical Preparations
Antioxidants
Mutation
Genes
hemiasterlin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Mitochondrial dysfunction confers resistance to multiple drugs in Caenorhabditis elegans. / Zubovych, Iryna O.; Straud, Sarah; Roth, Michael G.

In: Molecular Biology of the Cell, Vol. 21, No. 6, 15.03.2010, p. 956-969.

Research output: Contribution to journalArticle

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