RRC ID 36637
著者 Rauthan M, Ranji P, Abukar R, Pilon M.
タイトル A Mutation in Caenorhabditis elegans NDUF-7 Activates the Mitochondrial Stress Response and Prolongs Lifespan via ROS and CED-4.
ジャーナル G3 (Bethesda)
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.
巻・号 5(8)
ページ 1639-48
公開日 2015-6-1
DOI 10.1534/g3.115.018598
PII g3.115.018598
PMID 26038366
PMC PMC4528320
MeSH Alleles Amino Acid Sequence Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / antagonists & inhibitors Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Calcium-Binding Proteins / metabolism* Chaperonin 60 / genetics Chaperonin 60 / metabolism Electron Transport Complex I / genetics Electron Transport Complex I / metabolism Fatty Acids, Monounsaturated / pharmacology Fluvastatin Glutaral / analogs & derivatives Glutaral / metabolism Indoles / pharmacology Larva / growth & development Larva / metabolism Longevity Mitochondria / drug effects Mitochondria / metabolism* Molecular Sequence Data RNA Interference RNA, Small Interfering / metabolism Reactive Oxygen Species / metabolism* Stress, Physiological Transcription Factors / antagonists & inhibitors Transcription Factors / genetics Transcription Factors / metabolism Unfolded Protein Response / drug effects
IF 2.781
引用数 13
WOS 分野 GENETICS & HEREDITY
リソース情報
線虫 tm1436