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

Abstract

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