Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MetaboLights MTBLS1223 - GNPS NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome (Intracellular UPLC-MS assay)

ABSTRACT:

Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in C. elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WRN syndrome is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.

Intracellular UPLC-MS assay protocols and data are reported in the current study MTBLS1223.

Extracellular UPLC-MS assay protocols and data are reported in MTBLS1221.

INSTRUMENT(S): ACQUITY UPLC|1001761

ORGANISM(S): Homo Sapiens|9606

SUBMITTER: Sofie Lautrup

PROVIDER: MSV000085809 | GNPS | Wed Jul 22 11:19:00 BST 2020

REPOSITORIES: GNPS

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

Project description:Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in C. elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WRN syndrome is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.

2020-01-13 | PXD015644 | Pride

NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome (Extracellular UPLC-MS assay)

Project description:Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in C. elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WRN syndrome is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes. Extracellular UPLC-MS assay protocols and data are reported in the current study <a href=https://www.ebi.ac.uk/metabolights/MTBLS1221 target=_blank>MTBLS1221</a>.Intracellular UPLC-MS assay protocols and data are reported in <a href=https://www.ebi.ac.uk/metabolights/MTBLS1223 target=_blank>MTBLS1223</a>.

2019-10-17 | MTBLS1221 | MetaboLights

NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome (Intracellular UPLC-MS assay)

Project description:Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in C. elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WRN syndrome is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes. Intracellular UPLC-MS assay protocols and data are reported in the current study <a href=https://www.ebi.ac.uk/metabolights/MTBLS1223 target=_blank>MTBLS1223</a>.Extracellular UPLC-MS assay protocols and data are reported in <a href=https://www.ebi.ac.uk/metabolights/MTBLS1221 target=_blank>MTBLS1221</a>.

2019-10-17 | MTBLS1223 | MetaboLights

NAD+ repletion inhibits accelerated aging in Werner syndrome through the restoration of mitophagy

Project description:Metabolic dysfunction is a primary feature of the premature aging Werner syndrome (WS), a heritable human disease caused by mutations in the gene encoding the DNA helicase Werner (WRN). However, the relationship between WRN mutation and its severe metabolic phenotypes is unclear. Here we report mitochondrial dysfunction and depletion of NAD+, a fundamental ubiquitous cofactor, in WS patient samples and WS animal models. NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably delays accelerated aging, including stem cell dysfunction in both C. elegans and Drosophila models of WS. Mechanistically, WRN physically binds to a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) and facilitates its NAD+ production. Our findings reveal an unprecedented anti-aging mechanism of WRN that integrates its new function of NAD+ synthesis to coordinate mitochondrial maintenance and energy expenditure, and suggest therapeutic potential.

2019-08-16 | GSE108968 | GEO

NAD+ supplementation counteracts senescence mediated by STING in Ataxia Telangiectasia models by improving mitophagy (Human)

Project description:Senescence phenotypes and mitochondrial dysfunction are implicated in aging and neurodegeneration, and in the premature aging disease, including A-T. Loss of mitochondrial function can drive age-related decline in the brain, but little is known about whether improving mitochondrial homeostasis alleviates senescence phenotypes. Here we demonstrate impaired mitochondrial function and increased senescence growth arrest with senescence-associated secretory phenotype (SASP) in A-T patient fibroblasts, and in ATM-deficient cells and mice. We find that boosting intracellular NAD+ levels with nicotinamide riboside (NR) reduces senescence, suppresses neuroinflammation, and improves motor function in Atm-/- mice. We further show that the senescence responses are mediated by stimulator of interferon genes (STING), which is activated by cytoplasmic mtDNA and that NR prevents senescence and neuroinflammation through stimulation of mitophagy. Our findings suggest a pivotal role for mitochondrial dysfunction induced senescence in A-T pathogenesis, and that enhancing mitophagy is a potential therapeutic intervention.

2021-05-25 | GSE152287 | GEO

NAD+ supplementation counteracts senescence mediated by STING in Ataxia Telangiectasia models by improving mitophagy (Mouse)

2021-05-25 | GSE152286 | GEO

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling [HumanHT-12 V4.0]

Project description:Cockayne syndrome (CS) is a rare premature aging disease, which in the majority of cases is caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and die by 12 years of age on average. The CS proteins are involved in transcription and DNA repair, including a specialized form of DNA repair called transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, likely contributing to the severe premature aging phenotype of this disease. Our cross-species transciptomic analysis in CS postmortem brain tissue, CS mouse and C. elegans models showed that mitochondrial dysfunction is indeed a common feature in CS. Interestingly, the restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the C. elegans models of CS, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. We proceeded to perform molecular studies on cerebellar samples obtained from CS patients. We found that these patients exhibited molecular signatures of dysfunctional mitochondrial dynamics that can be corrected with NAD+ supplementation in primary cells with depleted CSA or CSB. Our study provides support for the interconnection between two major aging theories, DNA damage and mitochondrial dysfunction. Together these two agents contribute to an accelerated aging program that can be averted by NAD+ supplementation.

2020-12-22 | GSE144557 | GEO

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling [Agilent-020186 array]

2020-12-22 | GSE144556 | GEO

A High-Fat Diet and NAD+ Rescue Premature Aging in Cockayne Syndrome

Project description:Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in the genes encoding the DNA repair proteins CSA or CSB. Csbm/m mice were given a high-fat, caloric-restricted or resveratrol-supplemented diet. The high-fat diet rescued the phenotype of Csbm/m mice at the metabolic, transcriptomic and behavioral levels. Additional analysis suggests that the premature aging seen in CS mice, nematodes and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high-fat diet; and β-hydroxybutyrate, PARP inhibition, or NAD+ supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB is able to displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD+, through the deacetylase SIRT1 and suggests possible interventions for CS.

2014-12-22 | GSE62194 | GEO

the effect of UMI-77 on HGPS-MSCs gene expression during cellular senescence

Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging-related phenotypes, making it a disease model for physiological aging. The cellular machinery mediating age-associated hallmarks in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS treatment. In this study, we showed that deficiencies in mitophagy impaired mitochondrial quality and contributed to cellular phenotypes associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS-MSCs). Mechanistically, we discovered that mitophagy affected the aging-related phenotypes of HGPS-MSCs by inhibiting the cGAS-STING-NF-ĸB pathway and the downstream transcription of senescence-associated secretory phenotype (SASP). Furthermore, by utilizing UMI-77, an effective inducer of mitophagy, we showed that mitophagy induction can alleviate aging-associated phenotypes in both HGPS mice and naturally aged mice. In summary, our results uncover that mitophagy defects mediate mitochondrial dysfunction and aging-associated phenotypes in HGPS models, highlight the function of mitochondrial homeostasis in HGPS progression, and suggest that mitophagy could be exploited as a promising therapeutic target for both HGPS and aging.

2024-08-26 | GSE243251 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data