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

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.

DAF-16/Foxo suppresses the transgenerational sterility ofprg-1piRNA mutants via a systemic small RNA pathway

“…Analysis of the RNA-seq data revealed a greater than two-fold downregulation of the putitative H3K79 methyltransferase dot-1 and a greater than twofold upregulation for three histone genes (his-12, his- 16, his-43), the putative membrane transporter pgp-4 and T23G4.2, a homologue of the human mitochondrial lon pepitdase 1. However, these genes were not previously identified as DAF-16 targets (60,61). We therefore conclude that loss of daf-2 does not trigger strong changes to transcription of DAF-16 targets known to be involved in RNAi or transcriptional silencing pathways.…”

“…Adenosine deaminases modify double stranded RNAs by converting adenine to inosine, which results in dsRNA destruction (58) and therefore precludes dsRNA processing into 1 o siRNAs by RDE-4/DCR-1 and subsequent creation of 2 o 22G RNAs (59). To investigate potential daf-2-dependent changes in dsRNA processing, we re-analysed previously published daf-2 RNA-seq data (60) and lists of previously defined daf-16dependent loci based on RNA microarrays (61). Loss of adenosine deaminase activity results in targeting of endogenous dsRNA by the RNAi machinery (59), which is one possible mechanism by which loss of daf-2 could drive changes in dsRNA processing.…”

Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy

“…We reasoned that transcription factors whose depletion reduce the induction of the UPR mt in sgk-1 mutants might be implicated in the activation of different pro-survival pathways responsible for the long lifespan conferred by PHB depletion to TORC2 mutants [14]. Several transcription factors have been involved in the maintenance of mitochondrial homeostasis and lifespan, including DAF-16, SKN-1, HIF-1 and HSF-1 [34, 40, 51–58]. Moreover, the UPR mt promotes longevity by activating HIF-1, DAF-16 and SKN-1 [58].…”

Induction of RNA interference byC. elegansmitochondrial dysfunction via the DRH-1/RIG-I homologue RNA helicase and the EOL-1/RNA decapping enzyme

“…The eol-1 RNA decapping gene was also strongly induced in virally infected and mitochondrial mutant C. elegans ( Supplemental Table S1). We selected eol-1 for detailed analysis because a. it is conserved from yeast to mammals ( Figure 2B), b. eol-1 expression is induced by multiple mitochondrial mutations as well as in a eri-6; adr-1/2 enhanced RNAi mutant that desilences endogenous retroviruses and retrotransposons (Fischer and Ruvkun, 2020;Senchuk et al, 2018), c. the induction of eol-1 by Orsay virus infection is dependent on drh-1 (Sowa et al, 2020), and d. the human orthologue of EOL-1, DXO represses hepatitis C virus replication (Amador-Canizares et al, 2018). C. elegans eol-1 was initially identified as a mutant that enhanced olfactory learning after Pseudomonas aeruginosa infection (Shen et al, 2014).…”