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

Multi-omics analysis identifies essential regulators of mitochondrial stress response in two wild-type C. elegans strains

“…When analyzing either transcriptomic or proteomic data, we observed a number of shared and strain-specific regulations of different pathways and gene sets. Genes involved in lipid metabolism, proteolysis and stress response were upregulated in both worms upon Dox at the transcript level, which is consistent with the results of previous studies activating UPRmt via other inducers in N2 worms (Liu et al 2014;Pellegrino et al 2014;Sorrentino et al 2017;Liu et al 2020;Li et al 2021). Of note, after we integrated transcriptome and proteome profiles, we observed more strain-specific alterations upon Dox.…”

“…At transcript level, we observed a common effect of Dox on genes involved in various mitochondrial functions. Overall energy-consuming pathways were attenuated, including mitochondrial translation (Houtkooper et al 2013), consistent with reported observations in worms with mitochondrial stress induced by other stressors (Nargund et al 2015;Melber and Haynes 2018;Li et al 2021). Moreover, we observed a metabolic remodeling upon Dox in both worm strains, in which FAO genes were significantly upregulated in both worm strains, suggesting a switch to lipid breakdown to fuel energy production.…”

“…Through this approach, we uncovered shared and strain-specific effects of Dox, and important pathways/regulators that are involved in Doxinduced mitochondrial stress response and lifespan extension. Previously, we have showed the robust activation of UPRmt by administering Dox to N2 worms (Houtkooper et al 2013;Li et al 2021). It remains, however, unknown whether Dox could also activate the UPRmt and prolong lifespan in other C. elegans strains.…”

Epigenetic codes of mitochondrial homeostasis

“…Organisms employ a variety of quality control mechanisms to detect and respond to mitochondrial stress. In this issue, Li et al 3 report that the conserved histone acetyltransferase CBP/p300 acts as a positive regulator of mitochondrial homeostasis.…”

Combinatorial Approach Using Caenorhabditis elegans and Mammalian Systems for Aging Research

“…The expression levels of HDAC , a mammalian histone deacetylase gene, positively correlate with those of UPR mt genes in primates. The histone lysine demethylases JMJD-1.2 and JMJD-3.1 promote longevity in mitochondrial mutant C. elegans by activating UPR mt via downstream histone acetyltransferase CBP-1 ( Li et al, 2021 ; Merkwirth et al, 2016 ). Consistently, Phf8 and Jmjd3 ( Kdm6b ) expression levels, i.e., the respective mouse homologs of jmjd-1.2 and jmjd-3.1 , as well as CBP / p300 , the mammalian homolog of cbp-1 , positively correlate with those of UPR mt genes and mouse lifespan.…”