Mitochondrial ubiquinone-mediated longevity is marked by reduced cytoplasmic mRNA translation.

Marte Molenaars,Georges E Janssens,Rob Jelier,Riekelt H Houtkooper,Alyson W MacInnes,Marco Lezzerini,Toon Santermans

doi:10.26508/lsa.201800082

Abstract

Mutations in the clk-1 gene impair mitochondrial ubiquinone biosynthesis and extend lifespan in C. elegans. We demonstrate here that this life extension is linked to the repression of cytoplasmic mRNA translation, independent of the alleged nuclear form of CLK-1. Clk-1 mutations inhibit polyribosome formation similarly to daf-2 mutations that dampen insulin signaling. Comparisons of total versus polysomal RNAs in clk-1(qm30) mutants reveal a reduction in the translational efficiencies of mRNAs coding for elements of the translation machinery and an increase in those coding for the oxidative phosphorylation and autophagy pathways. Knocking down the transcription initiation factor TAF-4, a protein that becomes sequestered in the cytoplasm during early embryogenesis to induce transcriptional silencing, ameliorates the clk-1 inhibition of polyribosome formation. These results underscore a prominent role for the repression of cytoplasmic protein synthesis in eukaryotic lifespan extension and suggest that mutations impairing mitochondrial function are able to exploit this repression similarly to reductions of insulin signaling. Moreover, this report reveals an unexpected role for TAF-4 as a repressor of polyribosome formation when ubiquinone biosynthesis is compromised.

Highlights

Slowing down mitochondrial metabolism is a well-known means of increasing the lifespan of multiple species (Dillin et al, 2002; Copeland et al, 2009; Houtkooper et al, 2013; Breitenbach et al, 2014)
This study was initiated following our previous observation that the polysome profiles of clk-1(qm30) mutants revealed the same repression of polysomes as in the daf-2 mutants (Essers et al, 2015)
We continued this line of inquiry by isolating and sequencing polysomal and total RNAs from clk-1(qm30) mutants and compared them with clk-1(qm30)+WT worms. These results demonstrated that compared with clk-1(qm30)+WT, very few mRNAs coding for components of the translation machinery such as initiation factors, elongation factors, and ribosomal proteins are present on clk-1 polyribosomes

Summary

Introduction

Slowing down mitochondrial metabolism is a well-known means of increasing the lifespan of multiple species (Dillin et al, 2002; Copeland et al, 2009; Houtkooper et al, 2013; Breitenbach et al, 2014). In addition to lifespan extension and decreased respiration, clk-1 (qm30) mutants are developmentally delayed and have reduced progeny (Felkai et al, 1999). Transgenic mice, rescued from embryonic lethality via the transgenic expression of mouse clk-1, with reduced Clk expression live longer and have smaller bodies than WT mice, demonstrating a conserved role for clk-1 in longevity across species (Takahashi et al, 2014). It is not fully understood how the reduction of UQ biosynthesis extends the lifespan of these animals

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Results

Conclusion