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4E-BP Extends Lifespan upon Dietary Restriction by Enhancing Mitochondrial Activity in Drosophila

Zid, Brian M. and Rogers, Aric N. and Katewa, Subhash D. and Vargas, Misha A. and Kolipinski, Marysia C. and Lu, Tony Au and Benzer, Seymour and Kapahi, Pankaj (2009) 4E-BP Extends Lifespan upon Dietary Restriction by Enhancing Mitochondrial Activity in Drosophila. Cell, 139 (1). pp. 149-160. ISSN 0092-8674. PMCID PMC2759400.

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Dietary restriction (DR) extends lifespan in multiple species. To examine the mechanisms of lifespan extension upon DR, we assayed genome-wide translational changes in Drosophila. A number of nuclear encoded mitochondrial genes, including those in Complex I and IV of the electron transport chain, showed increased ribosomal loading and enhanced overall activity upon DR. We found that various mitochondrial genes possessed shorter and less structured 5′UTRs, which were important for their enhanced mRNA translation. The translational repressor 4E-BP, the eukaryotic translation initiation factor 4E binding protein, was upregulated upon DR and mediated DR dependent changes in mitochondrial activity and lifespan extension. Inhibition of individual mitochondrial subunits from Complex I and IV diminished the lifespan extension obtained upon DR, reflecting the importance of enhanced mitochondrial function during DR. Our results imply that translational regulation of nuclear-encoded mitochondrial gene expression by 4E-BP plays an important role in lifespan extension upon DR.

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Additional Information:© 2009 Elsevier Inc. Received 15 December 2008; revised 25 March 2009; accepted 15 July 2009. Published: October 1, 2009. Available online 1 October 2009. This manuscript is dedicated to the memory of Seymour Benzer, who passed away in the interim between research and publication of the manuscript. We thank David Nicholls, Martin Brand, Judith Campisi, Gordon Lithgow, Nagendra Yadav, Paul Sternberg, Eric Schwarz, Eimear Kenny, and members of the Kapahi and Benzer Labs, for helpful discussions. We would also like to thank the Kimbrell, Lasko, Sonenberg, Tijan, Tower, and Hafen labs for donation of strains and antibodies. This work was funded by grants from the National Institutes of Health (S.B.), a T32 NIH training grant fellowship (A.R.), grants from the Ellison Medical Foundation, American Foundation for aging research, Hillblom foundation, a Nathan Shock Startup award, a gift from the Harold J. and Reta Haynes Family Foundation, and the NIH (RL1AAG032113, 1R21AG028241-01) (P.K.). The microarray work was supported by the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology.
Funding AgencyGrant Number
Ellison Medical FoundationUNSPECIFIED
American Foundation for Aging ResearchUNSPECIFIED
Hillblom FoundationUNSPECIFIED
Nathan Shoch Startup AwardUNSPECIFIED
Harold J and Reta Haynes Family FoundationUNSPECIFIED
Millard and Muriel Jacobs Genetics and Genomics LaboratoryUNSPECIFIED
Subject Keywords:humdisease; protein
Issue or Number:1
PubMed Central ID:PMC2759400
Record Number:CaltechAUTHORS:20091020-134240373
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Official Citation:4E-BP Extends Lifespan upon Dietary Restriction by Enhancing Mitochondrial Activity in Drosophila Zid, Brian M.; Rogers, Aric N.; Katewa, Subhash D.; Vargas, Misha A.; Kolipinski, Marysia C.; Lu, Tony Au; Benzer, Seymour; Kapahi, Pankaj doi:10.1016/j.cell.2009.07.034 (volume 139 issue 1 pp.149 - 160)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:16409
Deposited By: Joy Painter
Deposited On:26 Oct 2009 21:16
Last Modified:03 Oct 2019 01:11

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