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A conserved role of CBP/p300 in mitochondrial stress response and longevity
Author(s) -
Auwerx Johan,
Li Terytty Yang
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00128
Subject(s) - caenorhabditis elegans , biology , epigenetics , mitochondrion , histone , microbiology and biotechnology , acetylation , histone acetyltransferases , genetics , acetyltransferase , gene
Caenorhabditis elegans respond to mitochondrial stress by activating multiple stress defense pathways including the mitochondrial unfolded protein response (UPR mt ). Here we show that the inhibition of CBP‐1, the C. elegans ortholog of mammalian acetyltransferases CBP/p300, either through RNA interference or by pharmacological inhibitors, robustly attenuates mitochondrial perturbation‐ induced UPR mt activation and lifespan extension. Mechanistically, CBP‐1‐mediated histone acetylation acts in conjunction with histone demethylation to transcriptionally induce a broad spectrum of UPR mt genes. In mouse and human, transcript levels of CBP/p300 systematically correlate with the expression of UPR mt genes and mitochondrial modules, as well as with longevity. Furthermore, loss‐of‐function of CBP/p300 or their pharmacological inhibition disrupts the activation of the UPR mt , the mitochondrial network and energy homeostasis in mammalian cells. These results highlight an evolutionary conserved epigenetic mechanism that protects mitochondrial function and regulates longevity through the histone acetyltransferases CBP/p300. Support or Funding Information This work was supported by grants from the Ecole Polytechnique Fédérale de Lausanne and the European Research Council (ERC‐AdG‐787702). T.Y.L. was supported by the “Human Frontier Science Program” (LT000731/2018‐L).