Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction

PNAS (2010); doi: 10.1073/pnas.0911539107
http://www.pnas.org/content/early/2010/04/22/0911539107.abstract?sid=dd82ed34-e42b-414c-a0a7-00c65b3c86c0

Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction
Alberto Sanza,1,2,3, Mikko Soikkelia,1, Manuel Portero-Otínb, Angela Wilsona, Esko Kemppainena, George McIlroya, Simo Elliläa, Kia K. Kemppainena, Tea Tuomelaa, Matti Lakanmaaa, Essi Kivirantaa, Rhoda Stefanatosa, Eric Dufoura, Bettina Hutza, Alba Naudíb, Mariona Jovéb, Akbar Zeba, Suvi Vartiainena, Akemi Matsuno-Yagic, Takao Yagic, Pierre Rustind, Reinald Pamplonab, and Howard T. Jacobsa,2,3
+ Author Affiliations

aInstitute of Medical Technology and Tampere University Hospital, FI-33014 University of Tampere, Finland;
bDepartment of Experimental Medicine, University of Lleida-Institut de Recerca Biomèdica Lleida, 25008 Lleida, Spain;
cDivision of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; and
dInstitut National de la Santé et de la Recherche Médicale U676 and Université Paris 7, Faculté de Médecine Denis Diderot, Hôpital Robert Debré, Paris 75019 France
Edited by Gottfried Schatz, University of Basel, Reinach, Switzerland, and approved March 16, 2010 (received for review October 7, 2009)

↵1A.S. and M.S. contributed equally to this article.

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.

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