title: Loss of HMG-CoA reductase in C. elegans causes defects in protein prenylation and muscle mitochondria.
abstract: HMG-CoA reductase is the rate-limiting enzyme in the mevalonate pathway and the target of cholesterol-lowering statins. We characterized the C. elegans hmgr-1(tm4368) mutant, which lacks HMG-CoA reductase, and show that its phenotypes recapitulate that of statin treatment, though in a more severe form. Specifically, the hmgr-1(tm4368) mutant has defects in growth, reproduction and protein prenylation, is rescued by exogenous mevalonate, exhibits constitutive activation of the UPRer and requires less mevalonate to be healthy when the UPRmt is activated by a constitutively active form of ATFS-1. We also show that different amounts of mevalonate are required for different physiological processes, with reproduction requiring the highest levels. Finally, we provide evidence that the mevalonate pathway is required for the activation of the UPRmt.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Parmida
authors.initials: P
authors.lastname: Ranji
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Manish
authors.initials: M
authors.lastname: Rauthan
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pitot
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Marc
authors.initials: M
authors.lastname: Pilon
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics* / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure*; D017368:Protein Prenylation; D012098:Reproduction; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C548052:ATFS-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D014157:Transcription Factors; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid