HSF-1 promotes longevity through ubiquilin-1 dependent mitochondrial remodelling
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ABSTRACT:
PROVIDER: PRJNA1008701 | ENA |
REPOSITORIES: ENA
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Project description:Impaired protein homeostasis promotes age-associated tissue dysregulation, presenting a need for therapeutic approaches that can restore proteome integrity. The heat shock factor HSF-1 is the master transcriptional regulator of proteostasis and regulates the expression of heat shock proteins (HSPs), which facilitate proper protein folding, localisation, and degradation. Increased HSF-1 activity can suppress proteotoxicity and enhance longevity across species. Studies into the mechanisms behind these beneficial effects have mostly focused on HSPs; however, the precise mechanisms by which increased HSF-1 activity extends lifespan are not known. To address this, we conducted an RNAi screen for genes that promote longevity, in C. elegans over expressing HSF-1 (hsf-1 OE). We found that ubiquilin-1 (ubql-1), a multifaceted shuttle protein that functions in protein degradation pathways is necessary for full lifespan extension in hsf-1OE worms. Surprisingly, we find that lack of ubql-1 does not impact proteostasis capacity, but does alter mitochondrial dynamics, in hsf-1 OE worms. These effects are independent of mitophagy or the mitochondrial unfolded protein response (mitoUPR) suggesting enhanced turnover of mitochondrial outer membrane proteins may be important for increased longevity via the HSF-1-ubiquilin-1 axis. Additionally, we reveal a role for ubql-1, a protein quality control regulator in regulating lipid homeostasis in hsf-1 OE animals. Lack of ubql-1 in hsf-1 OE animals supresses the expression of a key mitochondrial β-oxidation and lipid mobilization gene regulated by NHR-49 - acyl-CoA synthetase-2, ACS-2 amongst other genes. We propose that ubql-1 is required for mito-fusion and metabolic modulations that promote longevity in hsf-1 OE by interacting with NHR-49.
2024-10-17 | PXD044595 | Pride
Project description:In this experiment, we aimed to determine the gene expression changes associated with loss of UBQL-1 in wildtype and in worms overexpressing HSF-1 (hsf-1 OE).
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Project description:Mitochondrial activity is critical for cellular vitality and organismal longevity, yet underlying regulatory mechanisms spanning these different levels of organization remain elusive. From RNAi screens for mitochondrial biogenesis, we discovered NFYB-1, a subunit of the NF-Y transcriptional complex, as an ancestral regulator of mitochondrial function. NFYB-1 loss leads to reduced mitochondrial gene expression and oxygen consumption, mitochondrial fragmentation, disruption of mitochondrial stress pathways, and abolition of organismal longevity triggered by mitochondrial impairment. Multi-omics analysis reveals that NFYB-1 is a potent repressor of the ER stress response, as well as lysosomal prosaposin. Surprisingly, limiting prosaposin expression alters ceramide and cardiolipin pools, restores mitochondrial fusion, gene expression and longevity. Thus, the NFYB-1/prosaposin axis coordinates lysosomal to mitochondrial communication to enhance cellular mitochondrial function and organismal health.
2020-03-11 | GSE127917 | GEO
Project description:Heat shock factor 1 (HSF-1) and forkhead box O (FOXO) are key transcription factors that protect cells from various stresses. InCaenorhabditis elegans, HSF-1 and FOXO together promote a long life span when insulin/IGF-1 signaling (IIS) is reduced. However, it remains poorly understood how HSF-1 and FOXO cooperate to confer IIS-mediated longevity. Here, we show that prefoldin 6 (PFD-6), a component of the molecular chaperone prefoldin-like complex, relays longevity response from HSF-1 to FOXO under reduced IIS. We found that PFD-6 was specifically required for reduced IIS-mediated longevity by acting in the intestine and hypodermis. We showed that HSF-1 increased the levels of PFD-6 proteins, which in turn directly bound FOXO and enhanced its transcriptional activity. Our work suggests that the prefoldin-like chaperone complex mediates longevity response from HSF-1 to FOXO to increase the life span in animals with reduced IIS.
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Project description:Across eukaryotic species, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Mitochondrial dysfunction activates an unfolded protein response (UPRmt), a stress signaling mechanism designed to ensure mitochondrial homeostasis. Perturbation of mitochondria during larval development in C. elegans not only delays aging but also maintains UPRmt signaling, suggesting an epigenetic mechanism that modulates both longevity and mitochondrial proteostasis throughout life. Here we identify the conserved histone lysine demethylases jmjd-1.2/PHF8 and jmjd-3.1/JMJD3 as positive regulators of lifespan in response to mitochondrial dysfunction across species. Reduction-of-function of the demethylases potently suppresses longevity and UPRmt induction while gain-of-function is sufficient to extend lifespan in an UPRmt-dependent manner. A systems genetics approach in the BXD mouse reference population further indicated conserved roles of the mammalian orthologs in longevity and UPRmt signaling. These findings illustrate an evolutionary conserved epigenetic mechanism that determines the rate of aging downstream of mitochondrial perturbations.
2016-05-03 | GSE78990 | GEO
Project description:Mild deficits in mitochondrial function have been shown to increase lifespan in multiple species including worms, flies and mice. Here, we study three C. elegans mitochondrial mutants (clk-1, isp-1 and nuo-6) to identify overlapping genetic pathways that contribute to their longevity. We find that genes regulated by the FOXO transcription factor DAF-16 are upregulated in all three strains, and that the transcriptional changes present in these worms overlap significantly with the long-lived insulin-IGF1 signaling pathway mutant daf-2. We show that DAF-16 and multiple DAF-16 interacting proteins (MATH-33, IMB-2, CST-1/2, BAR-1) are required for the longevity of all three mitochondrial mutants. Our results suggest that the activation of DAF-16 in these mutants results from elevated levels of reactive oxygen species. Overall, this work reveals an overlapping genetic pathway required for longevity in three mitochondrial mutants, and, combined with previous work, demonstrates that DAF-16 is a downstream mediator of lifespan extension in multiple pathways of longevity.
2018-02-26 | GSE93724 | GEO
Project description:Mitochondrial clearance and HSF-1 activity are coupled to promote proteostasis capacity, organismal robustness and longevity in response to fasting
| PRJNA991709 | ENA
Project description:Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPRmt). However, how different layers of UPRmt regulators are orchestrated to transcriptionally activate the stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator for UPRmt activation, as well as for mitochondrial stress-induced immune response, amyloid-β aggregation reduction and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPRmt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPRmt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300.
2020-12-07 | GSE156830 | GEO
Project description:Mitochondrial activity is critical for cellular vitality and organismal longevity, yet underlying regulatory mechanisms spanning these different levels of organization remain elusive. From RNAi screens for mitochondrial biogenesis, we discovered NFYB-1, a subunit of the NF-Y transcriptional complex, as an ancestral regulator of mitochondrial function. NFYB-1 loss leads to reduced mitochondrial gene expression and oxygen consumption, mitochondrial fragmentation, disruption of mitochondrial stress pathways, and abolition of organismal longevity triggered by mitochondrial impairment. Multi-omics analysis reveals that NFYB-1 is a potent repressor of the ER stress response, as well as lysosomal prosaposin. Surprisingly, limiting prosaposin expression alters ceramide and cardiolipin pools, restores mitochondrial fusion, gene expression and longevity. Thus, the NFYB-1/prosaposin axis coordinates lysosomal to mitochondrial communication to enhance cellular mitochondrial function and organismal health.
2020-03-11 | PXD013233 | Pride