title: A Mutation in Caenorhabditis elegans NDUF-7 Activates the Mitochondrial Stress Response and Prolongs Lifespan via ROS and CED-4.
abstract: The mevalonate pathway is responsible for the synthesis of cholesterol, coenzyme Q, and prenyl groups essential for small GTPase modification and function, and for the production of dolichols important for protein glycosylation. Statins, i.e., cholesterol-lowering drugs that inhibit the rate-limiting enzyme in the mevalonate pathway, HMG-CoA reductase, are lethal to Caenorhabditis elegans even though this animal lacks the branch of the mevalonate pathway that leads to cholesterol synthesis. To better understand the effects of statins that are not related to cholesterol, we have adopted the strategy of isolating statin-resistant C. elegans mutants. Previously, we showed that such mutants often have gain-of-function mutations in ATFS-1, a protein that activates the mitochondrial unfolded protein response. Here, we describe the isolation of a statin-resistant mutant allele of the NDUF-7 protein, which is a component of complex I in the mitochondrial electron transport chain. The novel nduf-7(et19) mutant also exhibits constitutive and ATFS-1-dependent activation of the mitochondrial unfolded protein response (UPR(mt)) and prolonged life span, both of which are mediated through production of ROS. Additionally, lifespan extension, but not activation, of the mitochondrial unfolded protein response was dependent on the pro-apoptotic gene ced-4. We conclude that the nduf-7(et19) mutant allele causes an increase in reactive oxygen species that activate ATFS-1, hence UPR(mt)-mediated statin resistance, and extends life span via CED-4.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, S-405 30, Sweden.
authors.forename: Manish
authors.initials: M
authors.lastname: Rauthan
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, S-405 30, Sweden.
authors.forename: Parmida
authors.initials: P
authors.lastname: Ranji
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, S-405 30, Sweden.
authors.forename: Ragda
authors.initials: R
authors.lastname: Abukar
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, S-405 30, Sweden marc.pilon@cmb.gu.se.
authors.forename: Marc
authors.identifier: http://orcid.org/0000-0003-3919-2882
authors.initials: M
authors.lastname: Pilon
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D018834:Chaperonin 60 / Q000235:genetics / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D005976:Glutaral / Q000031:analogs & derivatives / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007814:Larva / Q000254:growth & development / Q000378:metabolism; D008136:Longevity; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013312:Stress, Physiological; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: C548052:ATFS-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; C089224:Ced-4 protein, C elegans; D018834:Chaperonin 60; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000077340:Fluvastatin; D042967:Electron Transport Complex I; D005976:Glutaral; C005261:mevaldic acid
keywords: C. elegans; UPRmt; aging; atfs-1; ced-4; mevalonate pathway; mitochondria; reactive oxygen species; statin