The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to...

Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPR^mt). However, how UPR^mt regulators are orchestrated to transcriptionally activate stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator of the UPR^mt, as well as mitochondrial stress-induced immune response, reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPR^mt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPR^mt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPR^mt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPR^mt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300.