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Mitochondrial Stress Induces Chromatin Reorganization to Promote Longevity and UPR(mt).

ABSTRACT: Organisms respond to mitochondrial stress through the upregulation of an array of protective genes, often perpetuating an early response to metabolic dysfunction across a lifetime. We find that mitochondrial stress causes widespread changes in chromatin structure through histone H3K9 di-methylation marks traditionally associated with gene silencing. Mitochondrial stress response activation requires the di-methylation of histone H3K9 through the activity of the histone methyltransferase met-2 and the nuclear co-factor lin-65. While globally the chromatin becomes silenced by these marks, remaining portions of the chromatin open up, at which point the binding of canonical stress responsive factors such as DVE-1 occurs. Thus, a metabolic stress response is established and propagated into adulthood of animals through specific epigenetic modifications that allow for selective gene expression and lifespan extension.

SUBMITTER: Tian Y

PROVIDER: S-EPMC4889216 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Mitochondrial Stress Induces Chromatin Reorganization to Promote Longevity and UPR(mt).

Tian Ye Y Garcia Gilberto G Bian Qian Q Steffen Kristan K KK Joe Larry L Wolff Suzanne S Meyer Barbara J BJ Dillin Andrew A

Cell 20160428 5

Organisms respond to mitochondrial stress through the upregulation of an array of protective genes, often perpetuating an early response to metabolic dysfunction across a lifetime. We find that mitochondrial stress causes widespread changes in chromatin structure through histone H3K9 di-methylation marks traditionally associated with gene silencing. Mitochondrial stress response activation requires the di-methylation of histone H3K9 through the activity of the histone methyltransferase met-2 and ...[more]

PMID: 27133166

Similar Datasets

Mitochondrial stress induces chromatin reorganization to promote longevity and UPRmt

Project description:Organisms respond to mitochondrial stress through the upregulation of an array of protective genes, often perpetuating an early response to metabolic dysfunction across a lifetime. We find that mitochondrial stress causes widespread changes in chromatin structure through histone H3K9 di-methylation marks traditionally associated with gene silencing. Mitochondrial stress response activation requires the di-methylation of histone H3K9 through the activity of the histone methyltransferase met-2 and the nuclear co-factor lin-65. While globally the chromatin becomes silenced by these marks, remaining portions of the chromatin open up, at which point the binding of canonical stress responsive factors such as DVE-1 occurs. Thus, a metabolic stress response is established and propagated into adulthood of animals through specific epigenetic modifications that allow for selective gene expression and lifespan extension.

2016-05-03 | GSE78252 | GEO

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis.

Project description:By causing mitochondrial DNA (mtDNA) mutations and oxidation of mitochondrial proteins, reactive oxygen species (ROS) leads to perturbations in mitochondrial proteostasis. Several studies have linked mtDNA mutations to metastasis of cancer cells but the nature of the mtDNA species involved remains unclear. Our data suggests that no common mtDNA mutation identifies metastatic cells; rather the metastatic potential of several ROS-generating mutations is largely determined by their mtDNA genomic landscapes, which can act either as an enhancer or repressor of metastasis. However, mtDNA landscapes of all metastatic cells are characterized by activation of the SIRT/FOXO/SOD2 axis of the mitochondrial unfolded protein response (UPRmt). The UPRmt promotes a complex transcription program ultimately increasing mitochondrial integrity and fitness in response to oxidative proteotoxic stress. Using SOD2 as a surrogate marker of the UPRmt, we found that in primary breast cancers, SOD2 is significantly increased in metastatic lesions. We propose that the ability of selected mtDNA species to activate the UPRmt is a process that is exploited by cancer cells to maintain mitochondrial fitness and facilitate metastasis.

| S-EPMC5542861 | biostudies-literature

The mitochondrial unfolded protein response (UPRmt) protects against osteoarthritis.

Project description:The mitochondrial unfolded protein response (UPRmt) is a mitochondrial-to-nuclear signaling pathway that is activated to maintain mitochondrial function when there is an accumulation of misfolded proteins within mitochondria. Mitochondrial function is essential for chondrocyte homeostasis, and mitochondrial dysfunction is a characteristic of osteoarthritis (OA). However, the role of the UPRmt in OA remains unclear. In the present study, the level of the UPRmt was examined in primary mouse chondrocytes subjected to different stresses and in the articular cartilage of OA model mice and OA patients. The relationship between UPRmt activation and OA progression was studied. The UPRmt was induced in primary mouse chondrocytes subjected to diverse stresses and in the cartilage of OA mice. Enhancement of the UPRmt with nicotinamide riboside (NR) significantly improved mitochondrial function, reduced chondrocyte death, attenuated OA pain, and ameliorated OA progression, and the protective effects decreased significantly in chondrocyte-specific Atf5 knockout (ATF5f/fCol2a1-CreERT2) mice. UPRmt induction was also identified in the articular cartilage of OA patients and was associated with reduced chondrocyte death, less severe hip pain, and lower levels of inflammation in synovial fluid. These findings identify the induction of the UPRmt in primary mouse chondrocytes exposed to pathological stresses and in the articular cartilage of OA model mice and OA patients. Enhancement of the UPRmt ameliorates OA progression, suggesting that the UPRmt exerts a protective effect against OA and may be a potential diagnostic and therapeutic strategy for OA.

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Temporal landscape of mitochondrial proteostasis governed by the UPRmt.

Project description:Breakdown of mitochondrial proteostasis activates quality control pathways including the mitochondrial unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond the up-regulation of chaperones and proteases, we have a limited understanding of how the UPRmt remodels and restores damaged mitochondrial proteomes. Here, we have developed a functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect the UPRmt's role in maintaining proteostasis during stress. We find essential roles for the UPRmt in both protecting and repairing proteostasis, with oxidative phosphorylation metabolism being a central target of the UPRmt. Transcriptome analyses together with MitoPQ reveal that UPRmt transcription factors drive independent signaling arms that act in concert to maintain proteostasis. Unidirectional interplay between the UPRmt and PINK1/Parkin mitophagy was found to promote oxidative phosphorylation recovery when the UPRmt failed. Collectively, this study defines the network of proteostasis mediated by the UPRmt and highlights the value of functional proteomics in decoding stressed proteomes.

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Exercise alters the mitochondrial proteostasis and induces the mitonuclear imbalance and UPRmt in the hypothalamus of mice.

Project description:The maintenance of mitochondrial activity in hypothalamic neurons is determinant to the control of energy homeostasis in mammals. Disturbs in the mitochondrial proteostasis can trigger the mitonuclear imbalance and mitochondrial unfolded protein response (UPRmt) to guarantee the mitochondrial integrity and function. However, the role of mitonuclear imbalance and UPRmt in hypothalamic cells are unclear. Combining the transcriptomic analyses from BXD mice database and in vivo experiments, we demonstrated that physical training alters the mitochondrial proteostasis in the hypothalamus of C57BL/6J mice. This physical training elicited the mitonuclear protein imbalance, increasing the mtCO-1/Atp5a ratio, which was accompanied by high levels of UPRmt markers in the hypothalamus. Also, physical training increased the maximum mitochondrial respiratory capacity in the brain. Interestingly, the transcriptomic analysis across several strains of the isogenic BXD mice revealed that hypothalamic mitochondrial DNA-encoded genes were negatively correlated with body weight and several genes related to the orexigenic response. As expected, physical training reduced body weight and food intake. Interestingly, we found an abundance of mt-CO1, a mitochondrial DNA-encoded protein, in NPY-producing neurons in the lateral hypothalamus nucleus of exercised mice. Collectively, our data demonstrated that physical training altered the mitochondrial proteostasis and induced the mitonuclear protein imbalance and UPRmt in hypothalamic cells.

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Mitochondrial Stress Induces Plant Resistance Through Chromatin Changes.

Project description:Plants respond more efficiently when confronted with previous similar stress. In the case of pathogens, this memory of a previous infection confers resistance to future ones, which possesses a high potential for agricultural purposes. Some of the defense elements involved in this resistance phenotype, as well as epigenetic mechanisms participating in the maintenance of the memory, are currently known. However, the intracellular cascade from pathogen perception until the establishment of the epigenetic memory is still unexplored. Here, through the induction of mitochondrial stress by exogenous applications of Antimycin A in Arabidopsis thaliana plants, we discovered and characterized a role of mitochondrial stress in plant-induced resistance. Mitochondrial stress-induced resistance (MS-IR) is effective locally, systemically, within generation and transgenerationally. Mechanistically, MS-IR seems to be mediated by priming of defense gene transcription caused by epigenetic changes. On one hand, we observed an increment in the deposition of H3K4me3 (a positive epigenetic mark) at the promoter region of the primed genes, and, on the other hand, the DNA (de)methylation machinery seems to be required for the transmission of MS-IR to the following generations. Finally, we observed that MS-IR is broad spectrum, restricting the colonization by pathogens from different kingdoms and lifestyles. Altogether, this evidence positions mitochondria as a prominent organelle in environment sensing, acting as an integrating platform to process external and internal signals, triggering the appropriate response, and inducing the epigenetic memory of the stress to better react against future stressful conditions.

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DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity.

Project description:Organisms are constantly challenged by stresses and privations and require adaptive responses for their survival. The forkhead box O (FOXO) transcription factor DAF-16 (hereafter referred to as DAF-16/FOXO) is a central nexus in these responses, but despite its importance little is known about how it regulates its target genes. Proteomic identification of DAF-16/FOXO-binding partners in Caenorhabditis elegans and their subsequent functional evaluation by RNA interference revealed several candidate DAF-16/FOXO cofactors, most notably the chromatin remodeller SWI/SNF. DAF-16/FOXO and SWI/SNF form a complex and globally co-localize at DAF-16/FOXO target promoters. We show that specifically for gene activation, DAF-16/FOXO depends on SWI/SNF, facilitating SWI/SNF recruitment to target promoters, to activate transcription by presumed remodelling of local chromatin. For the animal, this translates into an essential role for SWI/SNF in DAF-16/FOXO-mediated processes, in particular dauer formation, stress resistance and the promotion of longevity. Thus, we give insight into the mechanisms of DAF-16/FOXO-mediated transcriptional regulation and establish a critical link between ATP-dependent chromatin remodelling and lifespan regulation.

| S-EPMC3748955 | biostudies-literature

UPRmt activation improves pathological alterations in cellular models of mitochondrial diseases.

Project description:BackgroundMitochondrial diseases represent one of the most common groups of genetic diseases. With a prevalence greater than 1 in 5000 adults, such diseases still lack effective treatment. Current therapies are purely palliative and, in most cases, insufficient. Novel approaches to compensate and, if possible, revert mitochondrial dysfunction must be developed.ResultsIn this study, we tackled the issue using as a model fibroblasts from a patient bearing a mutation in the GFM1 gene, which is involved in mitochondrial protein synthesis. Mutant GFM1 fibroblasts could not survive in galactose restrictive medium for more than 3 days, making them the perfect screening platform to test several compounds. Tetracycline enabled mutant GFM1 fibroblasts survival under nutritional stress. Here we demonstrate that tetracycline upregulates the mitochondrial Unfolded Protein Response (UPRmt), a compensatory pathway regulating mitochondrial proteostasis. We additionally report that activation of UPRmt improves mutant GFM1 cellular bioenergetics and partially restores mitochondrial protein expression.ConclusionsOverall, we provide compelling evidence to propose the activation of intrinsic cellular compensatory mechanisms as promising therapeutic strategy for mitochondrial diseases.

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UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import in Caenorhabditis elegans.

Project description:As organisms develop, individual cells generate mitochondria to fulfill physiological requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS). Here, using the model organism Caenorhabditis elegans we demonstrate that ATFS-1 mediates an adaptable mitochondrial network expansion program that is active throughout normal development. Mitochondrial network expansion requires the relatively inefficient MTS in ATFS-1, which allows the transcription factor to be responsive to parameters that impact protein import capacity of the mitochondrial network. Increasing the strength of the ATFS-1 MTS impairs UPRmt activity by increasing accumulation within mitochondria. Manipulations of TORC1 activity increase or decrease ATFS-1 activity in a manner that correlates with protein synthesis. Lastly, expression of mitochondrial-targeted GFP is sufficient to expand the muscle cell mitochondrial network in an ATFS-1-dependent manner. We propose that mitochondrial network expansion during development is an emergent property of the synthesis of highly expressed mitochondrial proteins that exclude ATFS-1 from mitochondrial import, causing UPRmt activation.

| S-EPMC7817664 | biostudies-literature

ULP-2 SUMO protease regulates UPRmt and mitochondrial homeostasis in Caenorhabditis elegans.

Project description:Mitochondria are the powerhouses of cells, responsible for energy production and regulation of cellular homeostasis. When mitochondrial function is impaired, a stress response termed mitochondrial unfolded protein response (UPRmt) is initiated to restore mitochondrial function. Since mitochondria and UPRmt are implicated in many diseases, it is important to understand UPRmt regulation. In this study, we show that the SUMO protease ULP-2 has a key role in regulating mitochondrial function and UPRmt. Specifically, down-regulation of ulp-2 suppresses UPRmt and reduces mitochondrial membrane potential without significantly affecting cellular ROS. Mitochondrial networks are expanded in ulp-2 null mutants with larger mitochondrial area and increased branching. Moreover, the amount of mitochondrial DNA is increased in ulp-2 mutants. Downregulation of ULP-2 also leads to alterations in expression levels of mitochondrial genes involved in protein import and mtDNA replication, however, mitophagy remains unaltered. In summary, this study demonstrates that ULP-2 is required for mitochondrial homeostasis and the UPRmt.

| S-EPMC10929073 | biostudies-literature

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