Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A Surveillance Pathway Senses Leaked Mitochondrial DNA to Activate UPRmt and Promote Longevity

ABSTRACT: The mitochondrial unfolded protein response (UPRmt) is a critical mechanism for restoring cellular homeostasis and promoting longevity upon mitochondrial stress. However, the mechanisms that sense specific mitochondrial damage-associated signals and activate UPRmt remain largely unknown. Through a genome-wide RNAi screen in Caenorhabditis elegans, we identified the AT-hook protein LIN-15B as a mitochondrial stress sensor that detects leaked mitochondrial DNA (mtDNA) to activate UPRmt. We show that LIN-15B contains a mitochondrial targeting sequence (MTS) and a C-terminal domain with nuclear localization capability. Upon mitochondrial stress, LIN-15B accumulates on the outer mitochondrial membrane (OMM) and utilizes its C-terminal AT-hook domains to directly bind leaked mtDNA, with a preference for the AT-rich D-loop region. This interaction is required for the nuclear translocation of LIN-15B, which occurs independently of the canonical protein import sensor ATFS-1. Nuclear LIN-15B then activates a broad transcriptional program encompassing core UPRmt targets and a unique set of DNA repair genes. This surveillance pathway is critical for preserving mitochondrial network integrity and supporting organismal longevity. Our findings define a mitochondrial surveillance pathway in which LIN-15B senses displaced mtDNA, triggering a protective transcriptional response that promotes longevity, thus revealing a principle of cellular homeostasis monitoring via the detection of displaced self components.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE316187 | GEO | 2026/01/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transgenerational inheritance of increased mtDNA triggers mitochondrial UPR and modulates aging [WT vs. TGQ]

Project description:It would be evolutionarily beneficial if the information of transient stresses experienced by parents could be passed on to descendants as a forecast of the challenges to come. Here, we discovered that neuronal mitochondrial perturbations can transmit the mitochondrial unfolded protein response (UPRmt) to offspring for multiple generations in Caenorhabditis elegans. The transgenerational induction of UPRmt was caused by a higher level of maternally inherited mitochondrial DNA (mtDNA), which disturbed the balance of oxidative phosphorylation subunits encoded by mtDNA and nuclear DNA. Furthermore, an increase in mtDNA levels requires Wnt/b-catenin signaling to propagate across generations, thereby inducing the UPRmt and conferring increased lifespan and stress tolerance. Thus, transgenerational increase in mtDNA levels and the UPRmt enable offspring to live longer and confer stress tolerance.

2021-06-22 | GSE157031 | GEO

V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans

Project description:To adapt mitochondrial function to the ever-changing intra- and extra-cellular environment, multiple mitochondrial stress response (MSR) pathways, including the mitochondrial unfolded protein response (UPRmt), have evolved. However, how the mitochondrial stress signal is sensed and relayed to UPRmt transcription factors, such as ATFS-1 in Caenorhabditis elegans, remains largely unknown. Here, we show that a panel of vacuolar H+-ATPase (v-ATPase) subunits and the target of rapamycin complex 1 (TORC1) activity are essential for the cytosolic relay of mitochondrial stress to ATFS-1, and for the induction of the UPRmt. Mechanistically, mitochondrial stress stimulates v-ATPase/Rheb-dependent TORC1 activation, subsequently promoting ATFS-1 translation. Increased translation of ATFS-1 upon mitochondrial stress furthermore relies on a set of ribosomal components, but is independent of GCN-2/PEK-1 signaling. Finally, the v-ATPase and ribosomal subunits are required for mitochondrial surveillance and mitochondrial stress-induced longevity. These results reveal a v-ATPase-TORC1-ATFS-1 signaling pathway that links mitochondrial stress to the UPRmt through intimate crosstalks between multiple organelles.

2022-09-23 | GSE179517 | GEO

Two Conserved Histone Demethylases Regulate Mitochondrial Stress-Induced Longevity

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

The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress [C. elegans]

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 | GSE131611 | GEO

The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress [Mus musculus]

2020-12-07 | GSE131613 | GEO

The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress [HepG2]

2020-12-07 | GSE156830 | GEO

The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress [ChIP-seq]

2020-12-07 | GSE148328 | GEO

The nucleosome remodeling and deacetylase (NuRD) complex mediates the mitochondrial unfolded protein response and longevity in C. elegans

Project description:Mitochondrial stress during development causes widespread changes in chromatin structure to promote mitochondrial unfolded protein response (UPRmt), perpetuating an early response across a lifetime results in lifespan extension. We found that the nucleosome remodeling and deacetylase (NuRD) complex interact with the transcription factor DVE-1 to initiate the global chromatin condensation and induce the UPRmt in animals experienced with mild mitochondrial dysfunction. The condensed chromatin structure can be well maintained into later life that is beneficial for lifespan extension. Moreover, overexpression of the core component of the NuRD complex is sufficient to induce the UPRmt response and longevity in C. elegans. Thus, a transient mitochondrial stress response during early development is established and propagated into later life through the NuRD-dependent chromatin remodeling pathway to extend lifespan.

2020-07-31 | GSE143904 | GEO

Orphan precursor proteins and ROS activate the mitochondrial UPR_Interaction proteomics

Project description:The mitochondrial unfolded protein response (UPRmt) safeguards mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis. How the mitochondrial protein misfolding information is signalled to the nucleus as part of the human UPRmt remains unclear. Here, we showed that UPRmt signalling is carried out by the co-occurrence of two individual signals – ROS production in mitochondria and accumulation of orphan mitochondrial proteins in the cytosol. Combining proteomics and genetic approaches, we identified that mitochondrial protein misfolding caused the release of ROS into the intermembrane space (IMS), which was essential for UPRmt signalling. ROS released from mitochondria oxidized the cytosolic HSP40 protein DNAJA1 to enhance recruitment of cytosolic HSP70 to orphan mitochondrial proteins that accumulated in parallel in the cytosol due to mitochondrial import defect. This recruitment leads to the release of HSF1 from HSP70 and its subsequent translocation to the nucleus to activate transcription of UPRmt related genes. Strikingly, we found that combining ROS and the accumulation of orphan mitochondrial proteins in the cytosol was sufficient and necessary to activate the UPRmt. Our findings reveal that monitoring of ROS and orphan mitochondrial proteins in cytosol allows an elegant surveillance to control the UPRmt via HSF1 activation in human cells. These observations reveal a novel link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling.

2023-05-19 | PXD031948 | Pride

Orphan precursor proteins and ROS activate the mitochondrial UPR_Redox proteomics

2023-05-19 | PXD032011 | Pride