title: The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway.
abstract: Statins are cholesterol-lowering drugs that inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the synthesis of cholesterol via the mevalonate pathway. This pathway also produces coenzyme Q (a component of the respiratory chain), dolichols (important for protein glycosylation), and isoprenoids (lipid moieties responsible for the membrane association of small GTPases). We previously showed that the nematode Caenorhabditis elegans is useful to study the noncholesterol effects of statins because its mevalonate pathway lacks the sterol synthesis branch but retains all other branches. Here, from a screen of 150,000 mutagenized genomes, we isolated four C. elegans mutants resistant to statins by virtue of gain-of-function mutations within the first six amino acids of the protein ATFS-1, the key regulator of the mitochondrial unfolded protein response that includes activation of the chaperones HSP-6 and HSP-60. The atfs-1 gain-of-function mutants are also resistant to ibandronate, an inhibitor of an enzyme downstream of HMG-CoA reductase, and to gliotoxin, an inhibitor acting on a subbranch of the pathway important for protein prenylation, and showed improved mitochondrial function and protein prenylation in the presence of statins. Additionally, preinduction of the mitochondrial unfolded protein response in wild-type worms using ethidium bromide or paraquat triggered statin resistance, and similar observations were made in Schizosaccharomyces pombe and in a mammalian cell line. We conclude that statin resistance through maintenance of mitochondrial homeostasis is conserved across species, and that the cell-lethal effects of statins are caused primarily through impaired protein prenylation that results in mitochondria dysfunction.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden.
authors.forename: Manish
authors.initials: M
authors.lastname: Rauthan
authors.forename: Parmida
authors.initials: P
authors.lastname: Ranji
authors.forename: Nataly
authors.initials: N
authors.lastname: Aguilera Pradenas
authors.forename: Christophe
authors.initials: C
authors.lastname: Pitot
authors.forename: Marc
authors.initials: M
authors.lastname: Pilon
mesh_terms: D000483:Alleles; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D000077557:Ibandronic Acid; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D016296:Mutagenesis; D009154:Mutation; D041681:NIH 3T3 Cells; D018384:Oxidative Stress; D034622:RNA Interference; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: C548052:ATFS-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D004164:Diphosphonates; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D014157:Transcription Factors; D000077340:Fluvastatin; D002784:Cholesterol; D008798:Mevalonic Acid; D000077557:Ibandronic Acid