RRC ID 46746
Author Zubovych IO, Straud S, Roth MG.
Title Mitochondrial dysfunction confers resistance to multiple drugs in Caenorhabditis elegans.
Journal Mol. Biol. Cell
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 PKCepsilon.
Volume 21(6)
Pages 956-69
Published 2010-3-15
DOI 10.1091/mbc.e09-08-0673
PII E09-08-0673
PMID 20089839
PMC PMC2836976
MeSH Adenylate Kinase / metabolism Amino Acid Sequence Animals Caenorhabditis elegans / cytology* Caenorhabditis elegans / drug effects Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Drug Resistance / physiology* HeLa Cells Herbicides / pharmacology Humans Methacrylates / pharmacology Mitochondria / drug effects Mitochondria / genetics Mitochondria / metabolism* Mitochondrial Proteins / genetics Mitochondrial Proteins / metabolism Molecular Sequence Data Mutation Oligopeptides / chemistry Oligopeptides / pharmacology Paraquat / pharmacology Protein Kinase C / metabolism RNA Interference Reactive Oxygen Species / metabolism Repressor Proteins / genetics Repressor Proteins / metabolism Sequence Alignment Superoxide Dismutase / genetics Superoxide Dismutase / metabolism Thiazoles / pharmacology Tubulin Modulators / pharmacology
IF 3.905
Times Cited 32
C.elegans tm2312