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.

Induction of DNA repair proteins, Ref-1 and XRCC1, in adult rat brain following kainic acid-induced seizures.

We evaluated the expression of DNA repair proteins, redox factor-1 (Ref-1) and X-ray repair cross-complementing protein 1 (XRCC1), relevant to neurodegeneration following kainic acid-induced seizures in rats. Neurons with oxidative DNA damage exhibited increased expression and colocalization of Ref-1 and XRCC1. Upregulation of DNA repair proteins was also associated with p53 induction and TUNEL. Coexpression of DNA repair proteins and cell death markers following seizures suggests that the DNA repair response may not be sufficient to prevent excitotoxin-induced neurodegeneration.