Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptome (RNASeq) data of engineered human 293 cell with compromised subcellular NAD availability

ABSTRACT: The coenzyme NAD is consumed by signalling enzymes such as poly-ADP-ribose-polymerases (PARPs) and sirtuins. Understanding the mechanisms of aging-associated NAD decline and how cells cope with decreased NAD concentrations requires model systems reflecting chronic NAD deficiency. To evoke compartment-specific over-consumption of NAD, we have engineered cell lines expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum, and peroxisomes. Additionally, we have engineered cell lines that lack a functional gene for the human mitochondrial transporter SLC25A51 and the NAD biosynthesis enzyme NMNAT3. Isotope-tracer flux measurements and mathematical modelling showed that the lowered NAD concentration limits total NAD consumption kinetically. Moreover, NAD biosynthesis rate and capacity remained unchanged, thereby also precluding an increase of total NAD turnover. The chronic NAD deficiency was surprisingly well tolerated unless the mitochondria were targeted. Oxidative phosphorylation and glycolysis were little affected by NAD over-consumption in the other compartments. Likewise, peroxisomal NAD over-consumption was balanced by mitochondrial NAD decrease to maintain beta-oxidation of very long chain fatty acids in peroxisomes. We propose that subcellular NAD pools are interconnected, with mitochondria acting as a rheostat to facilitate NAD-dependent processes in organelles with excessive consumption.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255209 | GEO | 2024/02/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Mitochondrial PARP1 Regulates NAD+-dependent Poly ADP-ribosylation on Mitochondrial Nucleoids

Project description:Poly ADP-ribose (PAR) polymerases (PARPs) play fundamental roles in multiple DNA damage recognition and repair pathways. Persistent nuclear PARP activation causes cellular NAD+ depletion and exacerbates cellular aging. However, very little is known about mitochondrial PARP (mtPARP) and PARylation. The existence of mtPARP is controversial, and the biological roles for mtPARP induced mitochondrial PARylation are unclear. Here, we demonstrate the presence of PARP1 and PARylation in purified mitochondria. The addition of the PARP1 substrate NAD+ to isolated mitochondria induces PARylation which is suppressed by PARP inhibitor olaparib treatment. Mitochondrial PARylation was also evaluated by enzymatic labeling of terminal ADP-ribose (ELTA) labeling. To further confirm the presence of mtPARP1, we evaluated mitochondrial nucleoid PARylation by ADP ribose-chromatin affinity purification (ADPr-ChAP) . We observed that NAD+ stimulated PARylation and TFAM occupancy on the mtDNA regulatory region D-loop, inducing mtDNA transcription. These findings suggest that PARP1 is integrally involved in mitochondrial PARylation and NAD+ dependent mtPARP1 activity contributes to mtDNA transcription regulation.

2022-08-20 | GSE182533 | GEO

MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

Project description:The macro domain of the histone variant macroH2A1.1 is an evolutionary conserved ADP ribose-binding module of unknown physiological function. We demonstrate that during myogenic differentiation alternative splicing switches the expression of macroH2A1 from the non-ADP ribose binding to the binding isoform. While differentiation commitment is normal in cells lacking macroH2A1.1, we observe two phenotypes: diminished cell fusion correlating with reduced expression of adhesion and migration genes and reduced mitochondrial capacity. While the integrity of the ADP ribose-binding pocket is dispensable for gene regulation and fusion, it is critical to sustain optimal mitochondrial fatty acid oxidation. Rescue experiments using a pharmacological PARP-1 inhibitor and metabolomics support the idea that loss of macroH2A1.1 leads to PARP-1 activation and accelerated NAD+ consumption. As a consequence, the level of nicotinamide mononucleotide, the key metabolite for mitochondrial NAD+ pool regeneration, is reduced and sirtuins fail to maintain mitochondrial proteins in their hypoacetylated and active form. Our results support the idea that chromatin states containing the histone variant macroH2A1.1 contribute to optimal mitochondrial oxidative capacity by channeling the consumption of NAD+ from the nucleus to mitochondria in a manner largely independent on transcriptional regulation.

2017-08-18 | GSE70015 | GEO

MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

2017-08-18 | GSE78256 | GEO

IFNg Regulates NAD+ Metabolism in Human Monocytes

Project description:IFNg is an essential and pleiotropic activator of monocytes, but little is known about the changes in cellular metabolism required for IFNg-induced activation. We sought to characterize and elucidate the mechanisms by which IFNg reprograms monocyte metabolism to support its immunologic activities. Monocytes from healthy controls and patients with gain-of-function mutations in STAT1 (STAT1 GOF), or loss-of-function mutations in mitochondrial complex I (Leigh syndrome) and NADPH oxidase (chronic granulomatous disease, CGD) were metabolically phenotyped. We found that IFNg increased oxygen consumption rates (OCR), indicative of reactive oxygen species generation by both mitochondria and NADPH oxidase. Transcriptional profiling of human monocyte derived macrophages revealed that this oxidative phenotype was driven by an IFNg-induced reprogramming of NAD+ metabolism, which is dependent on nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ salvage to generate NADH and NADPH for oxidation by mitochondrial complex I and NADPH oxidase, respectively. Monocytes from patients with STAT1 GOF demonstrated higher than normal OCR, while monocytes from Leigh syndrome and CGD patients demonstrated reduced OCR. Chemical inhibition of NAMPT completely abrogated the IFNg-induced oxygen consumption, comparable to levels observed in CGD patients. These data identify an IFNg-induced, NAMPT-dependent, NAD+ salvage pathway that is critical for IFNg activation of human monocytes.

2021-12-31 | GSE176562 | GEO

Mus musculus

Project description:MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

| PRJNA287491 | ENA

Mus musculus

Project description:MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

| PRJNA313031 | ENA

MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

Project description:MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

| PRJNA313029 | ENA

Heiland2019 - NAD pathway model analysing the impact of NNMT on pathway dynamics and evolution

Project description:This is a detailed model of NAD biosynthesis and consumption representing pathway variances across kingdoms.

2019-07-26 | MODEL1905220001 | BioModels

Nicotinamide riboside supplementation confers modest effects on skeletal muscle metabolism without mitochondrial and acetyl-proteome remodelingNicotinamide riboside supplementation confers modest effects on skeletal muscle metabolism without mitochondrial and acetyl-proteome remodeling

Project description:Nicotinamide riboside supplements (NRS) have been touted as a nutraceutical that promotes cardiometabolic and musculoskeletal health by enhancing nicotinamide adenine dinucleotide (NAD+) biosynthesis, mitochondrial function and/or the activities of NAD-dependent sirtuin deacetylase enzymes. This investigation examined the impact of NRS on whole body energy homeostasis, skeletal muscle mitochondrial function, and corresponding shifts in the acetyl-lysine proteome, in the context of diet-induced obesity using C57BL/6NJ mice. The study also included a genetically-modified mouse model that imposes greater demand on sirtuin flux and associated NAD+ consumption, specifically within muscle tissues. In general, whole body glucose control was modestly improved by NRS when administered at the midpoint of a chronic high fat diet, but not when given as a preventative therapy upon initiation of the diet. Contrary to anticipated outcomes, the study produced little evidence that NRS increases tissue NAD+ levels, augments mitochondrial function and/or mitigates diet-induced hyperacetylation of the skeletal muscle proteome.

2022-02-17 | PXD027904 | Pride

Diverse intracellular pathogens activate Type III Interferon expression from peroxisomes

Project description:Detection of viral RNA in the cytosol of infected cells depends on RIG-I-lilke recptors that use MAVS as an adapter protein to activate antiviral gene expression. MAVS is tail-anchored on mitochondria, mitochondria-associated membranes and peroxisomes. As peroxisomal membrane proteins can be mistargeted to mitochondria in the absence of peroxisomes, we hypothesized that MAVS-dependent antiviral gene expression is activated more efficiently in this instance. Pex19 deficient skin firoblasts derived from a Zellweger syndrome patient lack peroxisomes. We introduced wild type Pex19 into these cells to restore peroxisome formation and assessed alterations in the gene expression profile of these cells after reovirus infection. 6 samples: 9 and 16 hrs after reovirus infection at an MOI of 100 total RNA was extracted from Pex19 reconstituted and deficient cell lines. Gene expression data was compared to uninfected cells.

2014-04-15 | E-GEOD-56783 | biostudies-arrayexpress

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