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Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity.

ABSTRACT: The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPRmt) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPRmt. HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPRmt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPRmt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity.

SUBMITTER: Shao LW

PROVIDER: S-EPMC7493924 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity.

Shao Li-Wa LW Peng Qi Q Dong Mingyue M Gao Kaiyu K Li Yumei Y Li Yi Y Li Chuan-Yun CY Liu Ying Y

Nature communications 20200915 1

The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPR<sup>mt</sup>) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial str ...[more]

PMID: 32934238

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Project description:Fungal blue-light photoreceptors have been proposed as integrators of light and oxidative stress. However, additional elements participating in the integrative pathway remain to be identified. In Trichoderma atroviride, the blue-light regulator (BLR) proteins BLR-1 and -2 are known to regulate gene transcription, mycelial growth, and asexual development upon illumination, and recent global transcriptional analysis revealed that the histone deacetylase-encoding gene hda-2 is induced by light. Here, by assessing responses to stimuli in wild-type and Δhda-2 backgrounds, we evaluate the role of HDA-2 in the regulation of genes responsive to light and oxidative stress. Δhda-2 strains present reduced growth, misregulation of the con-1 gene, and absence of conidia in response to light and mechanical injury. We found that the expression of hda-2 is BLR-1 dependent and HDA-2 in turn is essential for the transcription of early and late light-responsive genes that include blr-1, indicating a regulatory feedback loop. When subjected to reactive oxygen species (ROS), Δhda-2 mutants display high sensitivity whereas Δblr strains exhibit the opposite phenotype. Consistently, in the presence of ROS, ROS-related genes show high transcription levels in wild-type and Δblr strains but misregulation in Δhda-2 mutants. Finally, chromatin immunoprecipitations of histone H3 acetylated at Lys9/Lys14 on cat-3 and gst-1 promoters display low accumulation of H3K9K14ac in Δblr and Δhda-2 strains, suggesting indirect regulation of ROS-related genes by HDA-2. Our results point to a mutual dependence between HDA-2 and BLR proteins and reveal the role of these proteins in an intricate gene regulation landscape in response to blue light and ROS. Trichoderma atroviride is a free-living fungus commonly found in soil or colonizing plant roots and is widely used as an agent in biocontrol as it parasitizes other fungi, stimulates plant growth, and induces the plant defense system. To survive in various environments, fungi constantly sense and respond to potentially threatening external factors, such as light. In particular, UV light can damage biomolecules by producing free-radical reactions, in most cases involving reactive oxygen species (ROS). In T. atroviride, conidiation is essential for its survival, which is induced by light and mechanical injury. Notably, conidia are typically used as the inoculum in the field during biocontrol. Therefore, understanding the linkages between responses to light and exposure to ROS in T. atroviride is of major basic and practical relevance. Here, the histone deacetylase-encoding gene hda-2 is induced by light and ROS, and its product regulates growth, conidiation, blue light perception, and oxidative stress responses.

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Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity.

Publications

Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity.

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