title: Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction.
abstract: Mutations in mitochondrial oxidative phosphorylation complex I are associated with multiple pathologies, and complex I has been proposed as a crucial regulator of animal longevity. In yeast, the single-subunit NADH dehydrogenase Ndi1 serves as a non-proton-translocating alternative enzyme that replaces complex I, bringing about the reoxidation of intramitochondrial NADH. We have created transgenic strains of Drosophila that express yeast NDI1 ubiquitously. Mitochondrial extracts from NDI1-expressing flies displayed a rotenone-insensitive NADH dehydrogenase activity, and functionality of the enzyme in vivo was confirmed by the rescue of lethality resulting from RNAi knockdown of complex I. NDI1 expression increased median, mean, and maximum lifespan independently of dietary restriction, and with no change in sirtuin activity. NDI1 expression mitigated the aging associated decline in respiratory capacity and the accompanying increase in mitochondrial reactive oxygen species production, and resulted in decreased accumulation of markers of oxidative damage in aged flies. Our results support a central role of mitochondrial oxidative phosphorylation complex I in influencing longevity via oxidative stress, independently of pathways connected to nutrition and growth signaling.
authors.affiliation: Institute of Medical Technology and Tampere University Hospital, FI-33014 University of Tampere, Finland. alberto.sanz@uta.fi
authors.forename: Alberto
authors.initials: A
authors.lastname: Sanz
authors.forename: Mikko
authors.initials: M
authors.lastname: Soikkeli
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otín
authors.forename: Angela
authors.initials: A
authors.lastname: Wilson
authors.forename: Esko
authors.initials: E
authors.lastname: Kemppainen
authors.forename: George
authors.initials: G
authors.lastname: McIlroy
authors.forename: Simo
authors.initials: S
authors.lastname: Ellilä
authors.forename: Kia K
authors.initials: KK
authors.lastname: Kemppainen
authors.forename: Tea
authors.initials: T
authors.lastname: Tuomela
authors.forename: Matti
authors.initials: M
authors.lastname: Lakanmaa
authors.forename: Essi
authors.initials: E
authors.lastname: Kiviranta
authors.forename: Rhoda
authors.initials: R
authors.lastname: Stefanatos
authors.forename: Eric
authors.initials: E
authors.lastname: Dufour
authors.forename: Bettina
authors.initials: B
authors.lastname: Hutz
authors.forename: Alba
authors.initials: A
authors.lastname: Naudí
authors.forename: Mariona
authors.initials: M
authors.lastname: Jové
authors.forename: Akbar
authors.initials: A
authors.lastname: Zeb
authors.forename: Suvi
authors.initials: S
authors.lastname: Vartiainen
authors.forename: Akemi
authors.initials: A
authors.lastname: Matsuno-Yagi
authors.forename: Takao
authors.initials: T
authors.lastname: Yagi
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.forename: Howard T
authors.initials: HT
authors.lastname: Jacobs
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D031204:Caloric Restriction; D004331:Drosophila melanogaster / Q000201:enzymology / Q000502:physiology*; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D006651:Histocytochemistry; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: C493237:Ndi1 protein, S cerevisiae; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D042967:Electron Transport Complex I