Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates survival of developing retinal neurons
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA738469 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Despite mounting evidence that the mammalian retina is exceptionally reliant on proper NAD+ homeostasis for health and function, the specific roles of subcellular NAD+ pools in retinal development, maintenance, and disease remain obscure. Here, we show that deletion of the nuclear-localized NAD+ synthase nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1) in the developing murine retina causes early and severe degeneration of photoreceptors and select inner retinal neurons via multiple distinct cell death pathways. This severe phenotype is associated with disruptions to retinal central carbon metabolism, purine nucleotide synthesis, and amino acid pathways. Furthermore, large-scale transcriptomics reveals dysregulation of a collection of photoreceptor and synapse-specific genes in NMNAT1 knockout retinas prior to detectable morphological or metabolic alterations. Collectively, our study reveals previously unrecognized complexity in NMNAT1-associated retinal degeneration and suggests a yet-undescribed role for NMNAT1 in gene regulation during photoreceptor terminal differentiation.
2021-06-17 | GSE178312 | GEO
Project description: Not available
| S-EPMC8754432 | biostudies-literature
Project description:RNA polymerase II transcripts receive a protective 5ʹ m7G cap early during transcription. An alternative cap can be acquired when RNA pol II initiation uses the redox cofactor nicotinamide adenine dinucleotide (NAD) to generate NAD-capped RNAs. The biology of mammalian NAD-RNAs, including its turnover and physiological roles are not completely understood. Here we identify NUDT12 as a cytosolic decapping enzyme for NAD-RNAs. Structural, biochemical and functional studies reveal how homodimerization modulates specificity of NUDT12 for NAD-RNAs as substrate. NUDT12 is localized within a few discrete cytoplasmic granules that are distinct from P-bodies. We identity Bleomycin hydrolase (BLMH) as a factor that associates with NUDT12 in a large ~600 kDa dodecamer complex, and we demonstrate that BLMH is required for correct localization of NUDT12 into these granules. This complex is functional in human cell cultures, as artificial tethering of BLMH to a reporter mRNA results in downregulation of reporter expression, similar to that seen with tethering of NUDT12. Analysis of mouse liver transcriptome from the Nudt12 knockout mouse reveals that a select set of RNAs are regulated, including a significant upregulation of circadian clock transcripts. Given that NAD biosynthesis is under circadian control, our study points to a physiological role for the cytosolic surveillance of NAD-RNAs.
2019-12-25 | GSE138019 | GEO
Project description:We report uterine mRNA transcriptome sequencing of mice over-expressing human estrogen biosynthetic enzyme HSD17B1 (HSD17B1TG mice) present with adenomyosis phenotype.
2022-05-17 | GSE199492 | GEO
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
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
Project description:Decapping enzyme NUDT12 partners with BLMH for cytoplasmic surveillance of NAD-capped RNAs
| PRJNA574161 | ENA
Project description:The vitamin B12 processing enzyme, mmachc, is essential for zebrafish survival, growth and retinal morphology
| PRJNA540260 | ENA
Project description:In Cleomaceae species, NAD-malic enzyme (NAD-ME) was independently co-opted to participate in C4 photosynthesis. In C4 Cleome species, all NAD-ME genes (NAD-MEα, -ß1 and -ß2) were affected by C4 evolution and are expressed at higher levels than their C3 orthologs in Tarenaya hassleriana. In C3 Cleome, the NAD-ME housekeeping function is performed by two heteromers, NAD-MEα/ß1 and NAD-MEα/ß2, with similar biochemical properties and tissue occurrence. In the C4 species, Gynandropsis gynandra and Cleome angustifolia, this role is performed only by the NAD-MEα/ß2 heteromer. In these C4 species NAD-MEα/ß1 is preferentially present in leaves of the C4 species where is the predominant isoform. GgNAD-MEα/ß1 exhibits high catalytic efficiency and is differentially activated by the C4 intermediate aspartate. In C4 Cleome NAD-MEα/ß1 represents thus the C4-decarboxylase. GgNAD-MEß1and CaNAD-MEß1 are non-catalytic subunits but impart a stabilizing effect on the associated α-subunit. We conclude that in C4 Cleome the functions of NAD-ME as a TCA cycle associated enzyme and as a C4 photosynthetic decarboxylase coexist in BSC mitochondria and are performed by isoforms originated through associations of differentially adapted subunits.
2021-11-30 | PXD026547 | Pride
Project description:Molecular clocks in the periphery coordinate tissue-specific daily biorhythms by integrating input from the hypothalamic master clock and intracellular metabolic signals. One such key metabolic signal is the cellular concentration of NAD+, which oscillates along with its biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT). NAD+ levels feed back into the clock to influence rhythmicity of biological functions, yet whether this metabolic fine-tuning occurs ubiquitously across cell types and is a core clock feature is unknown. Here we show that NAMPT-dependent control over the molecular clock varies substantially between tissues. Brown adipose tissue (BAT) requires NAMPT to sustain the amplitude of the core clock, whereas rhythmicity in white adipose tissue (WAT) is only moderately dependent on NAD+ biosynthesis and the skeletal muscle clock is completely refractory to loss of NAMPT. In BAT and WAT, NAMPT differentially orchestrates oscillation of clock-controlled gene networks and the diurnality of metabolite levels. NAMPT coordinates the rhythmicity of TCA cycle intermediates in BAT, but not WAT, and loss of NAD+ abolishes these oscillations similarly to high fat diet (HFD)-induced circadian disruption. Adipose NAMPT depletion also improved the ability of animals to defend body temperature during cold stress but this is independent of time-of-day. Thus, our findings reveal that peripheral molecular clocks and metabolic biorhythms are shaped in a highly tissue-specific manner by NAMPT-dependent NAD+ synthesis.
2023-04-11 | GSE221550 | GEO