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A Mutation in Caenorhabditis elegans NDUF-7 Activates the Mitochondrial Stress Response and Prolongs Lifespan via ROS and CED-4

Artikel i vetenskaplig tidskrift
Författare Manish Rauthan
Parmida Ranji
Ragda Abukar
Marc Pilon
Publicerad i G3-Genes Genomes Genetics
Volym 5
Nummer/häfte 8
Sidor 1639-1648
ISSN 2160-1836
Publiceringsår 2015
Publicerad vid Institutionen för kemi och molekylärbiologi
Sidor 1639-1648
Språk en
Länkar dx.doi.org/10.1534/g3.115.018598
Ämnesord C. elegans, ced-4, atfs-1, aging, reactive oxygen species, statin, mevalonate pathway, UPRmt, UNFOLDED PROTEIN RESPONSE, MEVALONATE PATHWAY, C. ELEGANS, COMPLEX-I, ELECTRON-TRANSPORT, N-ACETYLCYSTEINE, LEIGH-SYNDROME, MIT MUTANTS, LONGEVITY, NEMATODE, Genetics & Heredity
Ämneskategorier Genetik

Sammanfattning

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 (UPRmt) 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 UPRmt-mediated statin resistance, and extends life span via CED-4.

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