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

Recent studies have propagated the model that the mitochondrial unfolded protein response (UPR mt ) is causal for lifespan extension from inhibition of the electron transport chain (ETC) in Caenorhabditis elegans . Here we report a genome-wide RNAi screen for negative regulators of the UPR mt . Lifespan analysis of nineteen RNAi clones that induce the hsp-6 p ::gfp reporter demonstrate differential effects on longevity. Deletion of atfs-1 , which is required for induction of the UPR mt , 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 UPR mt by gain of function mutations in atfs-1 fails to extend lifespan. These observations identify several new factors that promote mitochondrial homoeostasis and demonstrate that the UPR mt , as currently defined, is neither necessary nor sufficient for lifespan extension. The mitochondrial unfolded protein response (UPR mt ) has been linked to lifespan extension in Caenorhabditis elegans . Here, Bennett et al. identify negative regulators of the UPR mt and, surprisingly, find that the UPR mt is neither necessary nor sufficient for lifespan extension.