Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival.

ABSTRACT: A major cause of cell death caused by genotoxic stress is thought to be due to the depletion of NAD(+) from the nucleus and the cytoplasm. Here we show that NAD(+) levels in mitochondria remain at physiological levels following genotoxic stress and can maintain cell viability even when nuclear and cytoplasmic pools of NAD(+) are depleted. Rodents fasted for 48 hr show increased levels of the NAD(+) biosynthetic enzyme Nampt and a concomitant increase in mitochondrial NAD(+). Increased Nampt provides protection against cell death and requires an intact mitochondrial NAD(+) salvage pathway as well as the mitochondrial NAD(+)-dependent deacetylases SIRT3 and SIRT4. We discuss the relevance of these findings to understanding how nutrition modulates physiology and to the evolution of apoptosis.

SUBMITTER: Yang H

PROVIDER: S-EPMC3366687 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival.

Yang Hongying H Yang Tianle T Baur Joseph A JA Perez Evelyn E Matsui Takashi T Carmona Juan J JJ Lamming Dudley W DW Souza-Pinto Nadja C NC Bohr Vilhelm A VA Rosenzweig Anthony A de Cabo Rafael R de Cabo Rafael R Sauve Anthony A AA Sinclair David A DA

Cell 20070901 6

A major cause of cell death caused by genotoxic stress is thought to be due to the depletion of NAD(+) from the nucleus and the cytoplasm. Here we show that NAD(+) levels in mitochondria remain at physiological levels following genotoxic stress and can maintain cell viability even when nuclear and cytoplasmic pools of NAD(+) are depleted. Rodents fasted for 48 hr show increased levels of the NAD(+) biosynthetic enzyme Nampt and a concomitant increase in mitochondrial NAD(+). Increased Nampt prov ...[more]

PMID: 17889652

Similar Datasets

ID4 levels dictate the stem cell state in mouse spermatogonia.

Project description:Spermatogenesis is a classic model of cycling cell lineages that depend on a balance between stem cell self-renewal for continuity and the formation of progenitors as the initial step in the production of differentiated cells. The mechanisms that guide the continuum of spermatogonial stem cell (SSC) to progenitor spermatogonial transition and precise identifiers of subtypes in the process are undefined. Here we used an Id4-eGfp reporter mouse to discover that EGFP intensity is predictive of the subsets, with the ID4-EGFPBright population being mostly, if not purely, SSCs, whereas the ID4-EGFPDim population is in transition to the progenitor state. These subsets are also distinguishable by transcriptome signatures. Moreover, using a conditional overexpression mouse model, we found that transition from the stem cell to the immediate progenitor state requires downregulation of Id4 coincident with a major change in the transcriptome. Collectively, our results demonstrate that the level of ID4 is predictive of stem cell or progenitor capacity in spermatogonia and dictates the interface of transition between the different functional states.

| S-EPMC5312040 | biostudies-literature

Xrn1 Modulates Mitochondrial NAD Levels through NAD-Capped RNA Decay

Project description:Xrn1 Modulates Mitochondrial NAD Levels through NAD-Capped RNA Decay

2021-06-10 | MSV000087605 | MassIVE

Drp1 levels constitutively regulate mitochondrial dynamics and cell survival in cortical neurons.

Project description:Mitochondria exist as dynamic networks that are constantly remodeled through the opposing actions of fusion and fission proteins. Changes in the expression of these proteins alter mitochondrial shape and size, and may promote or inhibit the propagation of apoptotic signals. Using mitochondrially targeted EGFP or DsRed2 to identify mitochondria, we observed a short, distinctly tubular mitochondrial morphology in postnatal cortical neurons in culture and in retinal ganglion cells in vivo, whereas longer, highly interconnected mitochondrial networks were detected in cortical astrocytes in vitro and non-neuronal cells in the retina in vivo. Differential expression patterns of fusion and fission proteins, in part, appear to determine these morphological differences as neurons expressed markedly high levels of Drp1 and OPA1 proteins compared to non-neuronal cells. This finding was corroborated using optic tissue samples. Moreover, cortical neurons expressed several splice variants of Drp1 including a neuron-specific isoform which incorporates exon 3. Knockdown or dominant-negative interference of endogenous Drp1 significantly increased mitochondrial length in both neurons and non-neuronal cells, but caused cell death only in cortical neurons. Conversely, depletion of the fusion protein, Mfn2, but not Mfn1, caused extensive mitochondrial fission and cell death. Thus, Drp1 and Mfn2 in normal cortical neurons not only regulate mitochondrial morphology, but are also required for cell survival. The present findings point to unique patterns of Drp1 expression and selective vulnerability to reduced levels of Drp1 expression/activity in neurons, and demonstrate that the regulation of mitochondrial dynamics must be tightly regulated in neurons.

| S-EPMC2733949 | biostudies-literature

Role of alpha-synuclein protein levels in mitochondrial morphology and cell survival in cell lines.

Project description:?-Synuclein is highly associated with some neurodegeneration and malignancies. Overexpressing wild-type or mutant ?-synuclein promotes neuronal death by mitochondrial dysfunction, the underlying mechanisms of which remain poorly defined. It was recently reported that ?-synuclein expression could directly lead to mitochondrial fragmentation in vitro and in vivo, which may be due to ?-synuclein localization on mitochondria. Here, we applied a double staining method to demonstrate mitochondrial morphogenetic changes in cells overexpressed with ?-synuclein. We show that mitochondrial localization of ?-synuclein was increased following its overexpression in three distinct cell lines, including HeLa, SH-SY5Y, and PC12 cells, but no alteration in mitochondrial morphology was detected. However, ?-synuclein knockdown prevents MPP(+)-induced mitochondrial fragmentation in SH-SY5Y and PC12 cells. These data suggest that ?-synuclein protein levels hardly affect mitochondrial morphology in normal cell lines, but may have some influence on that under certain environmental conditions.

| S-EPMC3338674 | biostudies-other

Distinct functional domains of Ubc9 dictate cell survival and resistance to genotoxic stress.

Project description:Covalent modification with SUMO alters protein function, intracellular localization, or protein-protein interactions. Target recognition is determined, in part, by the SUMO E2 enzyme, Ubc9, while Siz/Pias E3 ligases may facilitate select interactions by acting as substrate adaptors. A yeast conditional Ubc9P(123)L mutant was viable at 36 degrees C yet exhibited enhanced sensitivity to DNA damage. To define functional domains in Ubc9 that dictate cellular responses to genotoxic stress versus those necessary for cell viability, a 1.75-A structure of yeast Ubc9 that demonstrated considerable conservation of backbone architecture with human Ubc9 was solved. Nevertheless, differences in side chain geometry/charge guided the design of human/yeast chimeras, where swapping domains implicated in (i) binding residues within substrates that flank canonical SUMOylation sites, (ii) interactions with the RanBP2 E3 ligase, and (iii) binding of the heterodimeric E1 and SUMO had distinct effects on cell growth and resistance to DNA-damaging agents. Our findings establish a functional interaction between N-terminal and substrate-binding domains of Ubc9 and distinguish the activities of E3 ligases Siz1 and Siz2 in regulating cellular responses to genotoxic stress.

| S-EPMC1489148 | biostudies-literature

The redox-sensitive transcription factor Nrf2 regulates murine hematopoietic stem cell survival independently of ROS levels.

Project description:Several studies have found that high levels of reactive oxidative species (ROS) are associated with stem cell dysfunction. In the present study, we investigated the role of nuclear factor erythroid-2-related factor 2 (Nrf2), a master regulator of the antioxidant response, and found that it is required for hematopoietic stem progenitor cell (HSPC) survival and myeloid development. Although the loss of Nrf2 leads to increased ROS in most tissues, basal ROS levels in Nrf2-deficient (Nrf2(-/-)) BM were not elevated compared with wild-type. Nrf2(-/-) HSPCs, however, had increased rates of spontaneous apoptosis and showed decreased survival when exposed to oxidative stress. Nrf2(-/-) BM demonstrated defective stem cell function, as evidenced by reduced chimerism after transplantation that was not rescued by treatment with the antioxidant N-acetyl cysteine. Gene-expression profiling revealed that the levels of prosurvival cytokines were reduced in Nrf2(-/-) HSPCs. Treatment with the cytokine G-CSF improved HSPC survival after exposure to oxidative stress and rescued the transplantation defect in Nrf2(-/-) cells despite increases in ROS induced by cytokine signaling. These findings demonstrate a critical role for Nrf2 in hematopoiesis and stem cell survival that is independent of ROS levels.

| S-EPMC3242719 | biostudies-literature

Abl-kinase-sensitive levels of ERK5 and its intrinsic basal activity contribute to leukaemia cell survival.

Project description:It is well established that the mitogen-activated protein kinase (MAPK) signal is regulated through phosphorylation-dependent activation by the three-tiered MAPK cascade. However, our studies on the interaction of the MAPK ERK5 with the tyrosine kinase c-Abl and its oncogenic variants v-Abl and Bcr/Abl disclosed an alternative aspect of regulation. Independent of the MAPK cascade, Abl kinases were able to regulate the cellular amount of ERK5, at least in part, by stabilizing the protein. The resulting level of ERK5 and its intrinsic basal activity, but not necessarily its activation, were essential and sufficient to increase transformation by v-Abl and to mediate survival of Bcr/Abl-expressing leukaemia cells. These results suggest that the ability to regulate the cellular abundance of ERK5 contributes to the oncogenic potential of Abl kinases.

| S-EPMC1299226 | biostudies-literature

Nutrient status shapes selfish mitochondrial genome dynamics across different levels of selection.

Project description:Cooperation and cheating are widespread evolutionary strategies. While cheating confers an advantage to individual entities within a group, competition between groups favors cooperation. Selfish or cheater mitochondrial DNA (mtDNA) proliferates within hosts while being selected against at the level of host fitness. How does environment shape cheater dynamics across different selection levels? Focusing on food availability, we address this question using heteroplasmic Caenorhabditis elegans. We find that the proliferation of selfish mtDNA within hosts depends on nutrient status stimulating mtDNA biogenesis in the developing germline. Interestingly, mtDNA biogenesis is not sufficient for this proliferation, which also requires the stress-response transcription factor FoxO/DAF-16. At the level of host fitness, FoxO/DAF-16 also prevents food scarcity from accelerating the selection against selfish mtDNA. This suggests that the ability to cope with nutrient stress can promote host tolerance of cheaters. Our study delineates environmental effects on selfish mtDNA dynamics at different levels of selection.

| S-EPMC7508553 | biostudies-literature

Effects of Drought on Nutrient Uptake and the Levels of Nutrient-Uptake Proteins in Roots of Drought-Sensitive and -Tolerant Grasses.

Project description:Climate change will increase drought in many regions of the world. Besides decreasing productivity, drought also decreases the concentration (%) of nitrogen (N) and phosphorous (P) in plants. We investigated if decreases in nutrient status during drought are correlated with decreases in levels of nutrient-uptake proteins in roots, which has not been quantified. Drought-sensitive (Hordeum vulgare, Zea mays) and -tolerant grasses (Andropogon gerardii) were harvested at mid and late drought, when we measured biomass, plant %N and P, root N- and P-uptake rates, and concentrations of major nutrient-uptake proteins in roots (NRT1 for NO₃, AMT1 for NH₄, and PHT1 for P). Drought reduced %N and P, indicating that it reduced nutrient acquisition more than growth. Decreases in P uptake with drought were correlated with decreases in both concentration and activity of P-uptake proteins, but decreases in N uptake were weakly correlated with levels of N-uptake proteins. Nutrient-uptake proteins per gram root decreased despite increases per gram total protein, because of the larger decreases in total protein per gram. Thus, drought-related decreases in nutrient concentration, especially %P, were likely caused, at least partly, by decreases in the concentration of root nutrient-uptake proteins in both drought-sensitive and -tolerant species.

| S-EPMC6027393 | biostudies-literature

p32 protein levels are integral to mitochondrial and endoplasmic reticulum morphology, cell metabolism and survival.

Project description:p32 [also known as HABP1 (hyaluronan-binding protein 1), gC1qR (receptor for globular head domains complement 1q) or C1qbp (complement 1q-binding protein)] has been shown previously to have both mitochondrial and non-mitochondrial localization and functions. In the present study, we show for the first time that endogenous p32 protein is a mitochondrial protein in HeLa cells under control and stress conditions. In defining the impact of altering p32 levels in these cells, we demonstrate that the overexpression of p32 increased mitochondrial fibrils. Conversely, siRNA-mediated p32 knockdown enhanced mitochondrial fragmentation accompanied by a loss of detectable levels of the mitochondrial fusion mediator proteins Mfn (mitofusin) 1 and Mfn2. More detailed ultrastructure analysis by transmission electron microscopy revealed aberrant mitochondrial structures with less and/or fragmented cristae and reduced mitochondrial matrix density as well as more punctate ER (endoplasmic reticulum) with noticeable dissociation of their ribosomes. The analysis of mitochondrial bioenergetics showed significantly reduced capacities in basal respiration and oxidative ATP turnover following p32 depletion. Furthermore, siRNA-mediated p32 knockdown resulted in differential stress-dependent effects on cell death, with enhanced cell death observed in the presence of hyperosmotic stress or cisplatin treatment, but decreased cell death in the presence of arsenite. Taken together, our studies highlight the critical contributions of the p32 protein to the morphology of mitochondria and ER under normal cellular conditions, as well as important roles of the p32 protein in cellular metabolism and various stress responses.

| S-EPMC3727215 | biostudies-literature

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