Activation of DAF-16/FOXO by reactive oxygen species contributes to longevity in long-lived mitochondrial mutants in Caenorhabditis elegans.

Megan M Senchuk,Zachary B Madaj,Jeremy M Van Raamsdonk,Claire E Schaar,Mary E Winn,Megan J Bowman,Benjamin K Johnson,Dylan J Dues,Michael Ristow

doi:10.1371/journal.pgen.1007268

Megan M Senchuk, Zachary B Madaj + Show 7 more

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https://doi.org/10.1371/journal.pgen.1007268

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Abstract

Mild deficits in mitochondrial function have been shown to increase lifespan in multiple species including worms, flies and mice. Here, we study three C. elegans mitochondrial mutants (clk-1, isp-1 and nuo-6) to identify overlapping genetic pathways that contribute to their longevity. We find that genes regulated by the FOXO transcription factor DAF-16 are upregulated in all three strains, and that the transcriptional changes present in these worms overlap significantly with the long-lived insulin-IGF1 signaling pathway mutant daf-2. We show that DAF-16 and multiple DAF-16 interacting proteins (MATH-33, IMB-2, CST-1/2, BAR-1) are required for the full longevity of all three mitochondrial mutants. Our results suggest that the activation of DAF-16 in these mutants results from elevated levels of reactive oxygen species. Overall, this work reveals an overlapping genetic pathway required for longevity in three mitochondrial mutants, and, combined with previous work, demonstrates that DAF-16 is a downstream mediator of lifespan extension in multiple pathways of longevity.

Highlights

Mitochondria serve a variety of critical functions within the cell including energy production, intracellular signaling and metabolism
To identify overlapping genetic pathways that contribute to longevity in long-lived mitochondrial mutants, we compared gene expression in clk-1, isp-1 and nuo-6 worms to wild-type worms using RNA sequencing (RNAseq)
As with the quantitative real-time RT-PCR results, we found that the long-lived mitochondrial mutants exhibit increased fluorescence from a Psod-3::GFP reporter strain [34], which is diminished by daf-16 RNAi (Fig 4F)

Summary

Introduction

Mitochondria serve a variety of critical functions within the cell including energy production, intracellular signaling and metabolism. Mutations in clk-1 were found to increase lifespan [1,2], and this gene was later found to encode a hydroxylase involved in the biosynthesis of ubiquinone [3]. This same screen identified nine other clk genes, all of which decrease mitochondrial function and increase lifespan [4]. An unbiased RNAi screen for genes that increase lifespan identified many genes involved in mitochondrial function [7]

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