The key role of the NAD biosynthetic enzyme nicotinamide mononucleotide adenylyltransferase in regulating cell functions

Fortunato, Carlo; Mazzola, Francesca; Raffaelli, Nadia

doi:10.1002/iub.2584

Cited by 17 publications

(12 citation statements)

References 97 publications

(264 reference statements)

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“…The fourth key gene, NMNAT3, is a member of the NMNAT family. NMNAT is another rate-limiting enzyme reversibly catalyzing the critical step in the biosynthesis of NAD from ATP and NMN ( 31 ). NMNAT was found to enhance NAD-dependent posttranslational modifications of p53 and deacetylation of p53 by inhibiting DNA damage-p53-caspase-3 signaling pathway, allowing glial cells with harmful mutations to survive and multiply ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

A prognostic NAD+ metabolism-related gene signature for predicting response to immune checkpoint inhibitor in glioma

Jiang

Zhou²,

Yan³

et al. 2023

Front. Oncol.

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BackgroundNicotinamide adenine dinucleotide (NAD+) metabolism is involved in a series of cancer pathogenesis processes, and is considered a promising therapeutic target for cancer treatment. However, a comprehensive analysis of NAD+ metabolism events on immune regulation and cancer survival has not yet been conducted. Here, we constructed a prognostic NAD+ metabolism-related gene signature (NMRGS) associated with immune checkpoint inhibitor (ICI) efficacy in glioma.Methods40 NAD+ metabolism-related genes (NMRGs) were obtained from the Reactome database and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Glioma cases with transcriptome data and clinical information were obtained from Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). NMRGS was constructed based on the calculated risk score using univariate analysis, Kaplan–Meier analysis, multivariate Cox regression, and nomogram. This NMRGS was verified in training (CGGA693) and validation (TCGA and CGGA325) cohorts. The immune characteristics, mutation profile, and response to ICI therapy were subsequently analyzed for different NMRGS subgroups.ResultsSix NAD+ metabolism-related genes, including CD38, nicotinamide adenine dinucleotide kinase (NADK), nicotinate phosphoribosyltransferase (NAPRT), nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3), poly(ADP-Ribose) polymerase family member 6 (PARP6), and poly(ADP-Ribose) polymerase family member 9 (PARP9), were ultimately used to construct a comprehensive risk model for glioma patients. Patients in the NMRGS-high group showed a poorer survival outcome than those in the NMRGS-low group. The area under curve (AUC) indicated that NMRGS has good potential in glioma prognostic prediction. A nomogram with improved accuracy was established based on independent prognostic factors (NMRGS score, 1p19q codeletion status, and WHO grade). Furthermore, patients in the NMRGS-high group showed a more immunosuppressive microenvironment, higher tumor mutation burden (TMB), higher human leucocyte antigen (HLA) expression and a more therapeutic response to ICI therapy.ConclusionsThis study constructed a prognostic NAD+ metabolism-related signature associated with the immune landscape in glioma, which can be used for guiding individualized ICI therapy.

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Section: Discussionmentioning

confidence: 99%

A prognostic NAD+ metabolism-related gene signature for predicting response to immune checkpoint inhibitor in glioma

Jiang

Zhou²,

Yan³

et al. 2023

Front. Oncol.

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“…Multiple pathways for NAD synthesis have been described in mammalian cells and tissues, including the de novo pathway from tryptophan, the salvage pathway through the recycling or incorporation of nicotinamide, and the Preiss–Handler pathway (Figure 1 ). Importantly, the expression of different enzymes of synthesis and degradation of NAD vary at the subcellular, cellular, and tissue levels (Camacho‐Pereira et al, 2016 ; Cambronne & Kraus, 2020 ; Fortunato et al, 2022 ; Liu, Su, et al, 2018 ; Zeidler, Chini, et al, 2022 ).…”

Section: Nad Metabolism In Agingmentioning

confidence: 99%

NAD metabolism: Role in senescence regulation and aging

Chini,

Cordeiro,

Tran

et al. 2023

Aging Cell

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The geroscience hypothesis proposes that addressing the biology of aging could directly prevent the onset or mitigate the severity of multiple chronic diseases. Understanding the interplay between key aspects of the biological hallmarks of aging is essential in delivering the promises of the geroscience hypothesis. Notably, the nucleotide nicotinamide adenine dinucleotide (NAD) interfaces with several biological hallmarks of aging, including cellular senescence, and changes in NAD metabolism have been shown to be involved in the aging process. The relationship between NAD metabolism and cellular senescence appears to be complex. On the one hand, the accumulation of DNA damage and mitochondrial dysfunction induced by low NAD+ can promote the development of senescence. On the other hand, the low NAD+ state that occurs during aging may inhibit SASP development as this secretory phenotype and the development of cellular senescence are both highly metabolically demanding. However, to date, the impact of NAD+ metabolism on the progression of the cellular senescence phenotype has not been fully characterized. Therefore, to explore the implications of NAD metabolism and NAD replacement therapies, it is essential to consider their interactions with other hallmarks of aging, including cellular senescence. We propose that a comprehensive understanding of the interplay between NAD boosting strategies and senolytic agents is necessary to advance the field.

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“…3 ). NMNAT occurs in three isoforms: NMNAT1 that is expressed in the nucleus, NMNAT2 that is expressed in the cytosol including axons, and NMNAT3 that is mostly expressed in mitochondria (Fortunato et al, 2022 ).…”

Section: Essentials Of Nad + Metabolism With Empha...mentioning

confidence: 99%

NAD⁺, Axonal Maintenance, and Neurological Disease

Alexandris,

Koliatsos

2023

Antioxidants & Redox Signaling

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Significance: The remarkable geometry of the axon exposes it to unique challenges for survival and maintenance. Axonal degeneration is a feature of peripheral neuropathies, glaucoma, and traumatic brain injury, and an early event in neurodegenerative diseases. Since the discovery of Wallerian degeneration (WD), a molecular program that hijacks nicotinamide adenine dinucleotide (NAD + ) metabolism for axonal self-destruction, the complex roles of NAD + in axonal viability and disease have become research priority. Recent Advances: The discoveries of the protective Wallerian degeneration slow (Wld S ) and of sterile alpha and TIR motif containing 1 (SARM1) activation as the main instructive signal for WD have shed new light on the regulatory role of NAD + in axonal degeneration in a growing number of neurological diseases. SARM1 has been characterized as a NAD + hydrolase and sensor of NAD + metabolism. The discovery of regulators of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) proteostasis in axons, the allosteric regulation of SARM1 by NAD + and NMN, and the existence of clinically relevant windows of action of these signals has opened new opportunities for therapeutic interventions, including SARM1 inhibitors and modulators of NAD + metabolism. Critical Issues: Events upstream and downstream of SARM1 remain unclear. Furthermore, manipulating NAD + metabolism, an overdetermined process crucial in cell survival, for preventing the degeneration of the injured axon may be difficult and potentially toxic. Future Directions: There is a need for clarification of the distinct roles of NAD + metabolism in axonal maintenance as contrasted to WD. There is also a need to better understand the role of NAD + metabolism in axonal endangerment in neuropathies, diseases of the white matter, and the early stages of neurodegenerative diseases of the central nervous system. Antioxid. Redox Signal. 39, 1167–1184.

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The key role of the NAD biosynthetic enzyme nicotinamide mononucleotide adenylyltransferase in regulating cell functions

Cited by 17 publications

References 97 publications

A prognostic NAD+ metabolism-related gene signature for predicting response to immune checkpoint inhibitor in glioma

A prognostic NAD+ metabolism-related gene signature for predicting response to immune checkpoint inhibitor in glioma

NAD metabolism: Role in senescence regulation and aging

NAD⁺, Axonal Maintenance, and Neurological Disease

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The key role of the NAD biosynthetic enzyme nicotinamide mononucleotide adenylyltransferase in regulating cell functions

Cited by 17 publications

References 97 publications

A prognostic NAD+ metabolism-related gene signature for predicting response to immune checkpoint inhibitor in glioma

A prognostic NAD+ metabolism-related gene signature for predicting response to immune checkpoint inhibitor in glioma

NAD metabolism: Role in senescence regulation and aging

NAD+, Axonal Maintenance, and Neurological Disease

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NAD⁺, Axonal Maintenance, and Neurological Disease