4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila.
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. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.
Zid
Brian M
BM
California Institute of Technology, Pasadena, CA 91125, USA.
Rogers
Aric N
AN
Katewa
Subhash D
SD
Vargas
Misha A
MA
Kolipinski
Marysia C
MC
Lu
Tony Au
TA
Benzer
Seymour
S
Kapahi
Pankaj
P
D020121:5' Untranslated Regions; D000818:Animals; D031204:Caloric Restriction; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008136:Longevity; D008928:Mitochondria / Q000378:metabolism*; D010448:Peptide Initiation Factors / Q000378:metabolism*; D014176:Protein Biosynthesis; D015854:Up-Regulation
D020121:5' Untranslated Regions; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors; C410006:Thor protein, Drosophila