A conserved role of CBP/p300 in mitochondrial stress response and longevity

Johan Auwerx,Terytty Yang Li

doi:10.1096/fasebj.2020.34.s1.00128

Johan Auwerx, Terytty Yang Li

Open Access

https://doi.org/10.1096/fasebj.2020.34.s1.00128

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Abstract

Caenorhabditis elegans respond to mitochondrial stress by activating multiple stress defense pathways including the mitochondrial unfolded protein response (UPRmt). 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 UPRmt activation and lifespan extension. Mechanistically, CBP‐1‐mediated histone acetylation acts in conjunction with histone demethylation to transcriptionally induce a broad spectrum of UPRmt genes. In mouse and human, transcript levels of CBP/p300 systematically correlate with the expression of UPRmt 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 UPRmt, 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 InformationThis 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).

Highlights

Mitochondria contribute to the harvesting of energy, and serve as key signaling hubs connecting numerous metabolic processes to essential cellular and organismal functions1
An antibiotic that inhibits mitochondrial translation and activates the MSR13, on the reduction of Aβ aggregates in GMC101 worms[50] (Fig. 4h, i). These results indicate that CBP-1 is essential for mitochondrial stress-induced immune response, lifespan extension and amyloid-β aggregation reduction in C. elegans
Dependent UPRmt effectors positively contribute to mitochondrial function recovery, improved immune response, enhanced proteostasis against amyloid-β aggregation, and lifespan extension

Summary

Introduction

Mitochondria contribute to the harvesting of energy, and serve as key signaling hubs connecting numerous metabolic processes to essential cellular and organismal functions1-. Mitochondria function as platforms to regulate programmed cell death and innate immune responses[1,8,9]. Multiple mitochondrial stress response (MSR) pathways have evolved to adapt mitochondrial function to the ever-changing cellular milieu and to a variety of extra-cellular cues[10,11]. The mitochondrial unfolded protein response (UPRmt), one of these MSR pathways, is triggered by mitochondrial-to‐nuclear communication, leading to an adaptive transcriptional response that promotes repair and recovery of the cell or organism from transient mitochondrial dysfunction[10,11,12,13]. Mitochondrial perturbations lead to cellular stress responses closely associated with innate immunity[9,16];

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