Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction.
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.
Sanz
Alberto
A
Institute of Medical Technology and Tampere University Hospital, FI-33014 University of Tampere, Finland. alberto.sanz@uta.fi
Soikkeli
Mikko
M
Portero-Otín
Manuel
M
Wilson
Angela
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Kemppainen
Esko
E
McIlroy
George
G
Ellilä
Simo
S
Kemppainen
Kia K
KK
Tuomela
Tea
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Lakanmaa
Matti
M
Kiviranta
Essi
E
Stefanatos
Rhoda
R
Dufour
Eric
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Hutz
Bettina
B
Naudí
Alba
A
Jové
Mariona
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Zeb
Akbar
A
Vartiainen
Suvi
S
Matsuno-Yagi
Akemi
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Yagi
Takao
T
Rustin
Pierre
P
Pamplona
Reinald
R
Jacobs
Howard T
HT
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*
C493237:Ndi1 protein, S cerevisiae; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D042967:Electron Transport Complex I