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

Abstract

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 implicate translational regulation of mitochondrial gene expression by 4E-BP which plays an important role in lifespan extension upon DR.

TOR and ageing: a complex pathway for a complex process

“…TOR-mediated phosphorylation of 4E-BPs disrupts an inhibitory interaction between 4E-BP and the initiation factor, eIF4E, promoting increased translation initiation. Consistent with an important function for 4E-BPs in ageing, enhanced levels of the inhibitor (or reduced expression of eIF4E) lead to lifespan extension in both worms and flies [41,65]. Epistasis analysis in flies suggests that activation of d4E-BP/Thor may be tightly linked to the longevity benefits of dietary restriction [65].…”

“…In the case of Drosophila, dietary restriction leads to d4E-BP-dependent increased translation (but not transcription) of several components of the mitochondrial electron transport chain [65]. In this context, the increased lifespan of the flies upon dietary restriction has been shown to be dependent on both d4E-BP and on some of the upregulated electron transport chain components [65]. The positive correlation of mitochondrial biogenesis and longevity has been shown in several organisms [92,93].…”

“…Inactivation of the TOR pathway increases mitochondrial number and induces mitochondrial gene expression via translational regulation, leading to enhanced cellular respiration. Similarly, enhanced d4E-BP1 activity in Drosophila melanogaster or S6K1 deletion in mouse results in increased mitochondrial biogenesis and in both cases results in lifespan extension [60,65]. In the case of Drosophila, dietary restriction leads to d4E-BP-dependent increased translation (but not transcription) of several components of the mitochondrial electron transport chain [65].…”

“…Similarly, enhanced d4E-BP1 activity in Drosophila melanogaster or S6K1 deletion in mouse results in increased mitochondrial biogenesis and in both cases results in lifespan extension [60,65]. In the case of Drosophila, dietary restriction leads to d4E-BP-dependent increased translation (but not transcription) of several components of the mitochondrial electron transport chain [65]. In this context, the increased lifespan of the flies upon dietary restriction has been shown to be dependent on both d4E-BP and on some of the upregulated electron transport chain components [65].…”

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

“…In contrast, Sir2 overexpression does not rescue parkin mutant phenotypes, and Sir2 deletion only inhibits the development of parkin mutants but not PINK1 mutants. Moreover, the mRNA expression of super oxide dismutase 2 (SOD2) and 4E-binding protein (4EBP), the FOXO target genes with mitochondrial protective roles (Kops et al, 2002;Puig et al, 2003;Tain et al, 2009;Zid et al, 2009), are substantially reduced in PINK1 mutants but are normal in parkin mutants (Koh et al, 2012), suggesting that Sir2 and FOXO act in mitochondrial protection in parallel with Parkin. Consistently, Sir2 and FOXO mutants exhibit DA neuron degeneration very similar to that of PINK1 mutants.…”