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 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.
Zubovych
Iryna O
IO
Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9038, USA.
Straud
Sarah
S
Roth
Michael G
MG
D000263:Adenylate Kinase / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000502:physiology*; D006367:HeLa Cells; D006540:Herbicides / Q000494:pharmacology; D006801:Humans; D008689:Methacrylates / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010269:Paraquat / Q000494:pharmacology; D000091402:Prohibitins; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D050257:Tubulin Modulators / Q000494:pharmacology
D029742:Caenorhabditis elegans Proteins; C473896:HTI-286; C551928:Har-1 protein, C elegans; D006540:Herbicides; D008689:Methacrylates; D024101:Mitochondrial Proteins; D009842:Oligopeptides; C000717328:PHB protein, human; C000717331:PHB2 protein, human; D000091402:Prohibitins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D013844:Thiazoles; D050257:Tubulin Modulators; C000717338:prohibitin 2, C elegans; C467070:hemiasterlin; C030517:myxothiazol; D013482:Superoxide Dismutase; D011493:Protein Kinase C; D000263:Adenylate Kinase; D010269:Paraquat