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Background  The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway activated by disruption of proteostasis in the mitochondria. This pathway has been proposed to influence lifespan, with studies suggesting that mitoUPR activation has complex effects on longevity.    Results  Here, we examined the contribution of the mitoUPR to the survival and lifespan of three long-lived mitochondrial mutants in  Caenorhabditis elegans  by modulating the levels of ATFS-1, the central transcription factor that mediates the mitoUPR. We found that  clk-1 ,  isp-1 , and  nuo-6  worms all exhibit an ATFS-1-dependent activation of the mitoUPR. While loss of  atfs-1  during adulthood does not affect lifespan in any of these strains, absence of  atfs-1  during development prevents  clk-1  and  isp-1  worms from reaching adulthood and reduces the lifespan of  nuo-6  mutants. Examining the mechanism by which deletion of  atfs-1  reverts  nuo-6  lifespan to wild-type, we find that many of the transcriptional changes present in  nuo-6  worms are mediated by ATFS-1. Genes exhibiting an ATFS-1-dependent upregulation in  nuo-6  worms are enriched for transcripts that function in stress response and metabolism. Consistent, with this finding, loss of  atfs-1  abolishes the enhanced stress resistance observed in  nuo-6  mutants and prevents upregulation of multiple stress response pathways including the HIF-1-mediated hypoxia response, SKN-1-mediated oxidative stress response and DAF-16-mediated stress response.    Conclusions  Our results suggest that in the long-lived mitochondrial mutant  nuo-6  activation of the mitoUPR causes  atfs-1- dependent changes in the expression of genes involved in stress response and metabolism, which contributes to the extended longevity observed in this mutant. This work demonstrates that the mitoUPR can modulate multiple stress response pathways and suggests that it is crucial for the development and lifespan of long-lived mitochondrial mutants.    Electronic supplementary material  The online version of this article (10.1186/s12915-018-0615-3) contains supplementary material, which is available to authorized users.

bmc biology

Mitochondrial unfolded protein response transcription factor ATFS-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways