Activation of the mitochondrial unfolded protein response does not predict longevity in Caenorhabditis elegans

Abstract

Recent studies have propagated the model that the mitochondrial unfolded protein response (UPRmt) is causal for lifespan extension from inhibition of the electron transport chain (ETC) in C. elegans. Here we report a genome-wide RNAi screen for negative regulators of the UPRmt. Lifespan analysis of nineteen RNAi clones that induce the hsp-6p::gfp reporter demonstrate differential effects on longevity. Deletion of atfs-1, which is required for induction of the UPRmt, fails to prevent lifespan extension from knockdown of two genes identified in our screen or following knockdown of the ETC gene cco-1. RNAi knockdown of atfs-1 also has no effect on lifespan extension caused by mutation of the ETC gene isp-1. Constitutive activation of the UPRmt by gain of function mutations in atfs-1 fails to extend lifespan. These observations identify several new factors that promote mitochondrial homeostasis and demonstrate that the UPRmt, as currently defined, is neither necessary nor sufficient for lifespan extension.

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

“…The percentage of candidate genes that directly affected lifespan at 25 °C (43.9%) was substantially higher than RNAi screens in C. elegans without a preselection criteria (<2%) (Lee et al ., 2003b; Hamilton et al ., 2005; Hansen et al ., 2005; Samuelson et al ., 2007) and within the range for screens that preselected candidates based on secondary C. elegans phenotypes, including developmental arrest (2–42%) (Chen et al ., 2007; Curran & Ruvkun, 2007), reproductive senescence (16%) (Wang et al ., 2014), thermal stress resistance (78%) (Munoz & Riddle, 2003), oxidative stress resistance (13–67%) (de Castro et al ., 2004; Kim & Sun, 2007), and activation of the mitochondrial unfolded‐protein response (53%) (Bennett et al ., 2014) (reviewed by Yanos et al ., 2012 and Sutphin & Korstanje, 2016). Tacutu et al .…”

Searching for the elusive mitochondrial longevity signal in C. elegans

“…Nevertheless we observed a complete block in UPR mt induction, based on expression of 3 different endogenous UPR mt target genes. Taken in combination with the failure of gain of function alleles in ATFS-1 to extend lifespan, as observed both by us and the Pilon lab, 18,25 these data greatly weaken the model that the UPR mt plays a direct role in promoting longevity in C. elegans.…”

“…The atfs-1(tm4525) allele prevented induction of the hsp-6 p ::gfp reporter as well as increased expression of hsp-6, hsp-60, and timm-23 following RNAi knockdown of cco-1 or mutation of isp-1 without influencing the lifespan extension associated with these interventions. 18 We note that this allele causes a truncated atfs-1 mRNA to be expressed, 15 so it is possible that residual ATFS-1 activity could be present. Nevertheless we observed a complete block in UPR mt induction, based on expression of 3 different endogenous UPR mt target genes.…”

“…Although conceptually similar screens had been performed previously, we identified dozens of novel genetic modifiers of UPR mt signaling using this approach. 18 We anticipated that a majority of the RNAi clones found to induce the hsp-6 p ::gfp and hsp-60 p ::gfp reporters should also extend lifespan. In contrast to this prediction, about half of the clones tested had no effect or significantly shortened lifespan.…”

New functional and biophysical insights into the mitochondrial Rieske iron-sulfur protein from genetic suppressor analysis inC. elegans

“…Although several mechanisms have been proposed, it was unclear precisely why this particular mutation, as well as other C. elegans strains with reduced mitochondrial function, live longer. 4,5 To gain additional insight into ISP-1-mediated mechanisms of lifespan control, we performed a genetic suppressor screen to identify mutations that could suppress the slow developmental rate of isp-1 (qm150) animals. We chose to focus initially on developmental rate, because this phenotype was much easier to score (2 d analysis compared with measuring lifespan, which requires several weeks of observation) and thereby enabled ready identification of suppressing mutations.…”