Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

NAD⁺ Metabolism and Diseases with Motor Dysfunction.

ABSTRACT: Neurodegenerative diseases result in the progressive deterioration of the nervous system, with motor and cognitive impairments being the two most observable problems. Motor dysfunction could be caused by motor neuron diseases (MNDs) characterized by the loss of motor neurons, such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease, or other neurodegenerative diseases with the destruction of brain areas that affect movement, such as Parkinson's disease and Huntington's disease. Nicotinamide adenine dinucleotide (NAD⁺) is one of the most abundant metabolites in the human body and is involved with numerous cellular processes, including energy metabolism, circadian clock, and DNA repair. NAD⁺ can be reversibly oxidized-reduced or directly consumed by NAD⁺-dependent proteins. NAD⁺ is synthesized in cells via three different paths: the de novo, Preiss-Handler, or NAD⁺ salvage pathways, with the salvage pathway being the primary producer of NAD⁺ in mammalian cells. NAD⁺ metabolism is being investigated for a role in the development of neurodegenerative diseases. In this review, we discuss cellular NAD⁺ homeostasis, looking at NAD⁺ biosynthesis and consumption, with a focus on the NAD⁺ salvage pathway. Then, we examine the research, including human clinical trials, focused on the involvement of NAD⁺ in MNDs and other neurodegenerative diseases with motor dysfunction.

SUBMITTER: Lundt S

PROVIDER: S-EPMC8625820 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction.

Project description:Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.

| S-EPMC7604620 | biostudies-literature

KL1333, a Novel NAD+ Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts.

Project description:Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), one of the most common maternally inherited mitochondrial diseases, is caused by mitochondrial DNA mutations that lead to mitochondrial dysfunction. Several treatment options exist, including supplementation with CoQ10, vitamins, and nutrients, but no treatment with proven efficacy is currently available. In this study, we investigated the effects of a novel NAD+ modulator, KL1333, in human fibroblasts derived from a human patient with MELAS. KL1333 is an orally available, small organic molecule that reacts with NAD(P)H:quinone oxidoreductase 1 (NQO1) as a substrate, resulting in increases in intracellular NAD+ levels via NADH oxidation. To elucidate the mechanism of action of KL1333, we used C2C12 myoblasts, L6 myoblasts, and MELAS fibroblasts. Elevated NAD+ levels induced by KL1333 triggered the activation of SIRT1 and AMPK, and subsequently activated PGC-1? in these cells. In MELAS fibroblasts, KL1333 increased ATP levels and decreased lactate and ROS levels, which are often dysregulated in this disease. In addition, mitochondrial functional analyses revealed that KL1333 increased mitochondrial mass, membrane potential, and oxidative capacity. These results indicate that KL1333 improves mitochondrial biogenesis and function, and thus represents a promising therapeutic agent for the treatment of MELAS.

| S-EPMC6041391 | biostudies-literature

Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction

Project description:Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly (ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short, and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.

| S-SCDT-EMBOJ-2019-103420P | biostudies-other

Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism.

Project description:NAD+, a co-enzyme involved in a great deal of biochemical reactions, has been found to be a network node of diverse biological processes. In mammalian cells, NAD+ is synthetized, predominantly through NMN, to replenish the consumption by NADase participating in physiologic processes including DNA repair, metabolism, and cell death. Correspondingly, aberrant NAD+ metabolism is observed in many diseases. In this review, we discuss how the homeostasis of NAD+ is maintained in healthy condition and provide several age-related pathological examples related with NAD+ unbalance. The sirtuins family, whose functions are NAD-dependent, is also reviewed. Administration of NMN surprisingly demonstrated amelioration of the pathological conditions in some age-related disease mouse models. Further clinical trials have been launched to investigate the safety and benefits of NMN. The NAD+ production and consumption pathways including NMN are essential for more precise understanding and therapy of age-related pathological processes such as diabetes, ischemia-reperfusion injury, heart failure, Alzheimer's disease, and retinal degeneration.

| S-EPMC7198709 | biostudies-literature

NAD+ Metabolism as an Emerging Therapeutic Target for Cardiovascular Diseases Associated With Sudden Cardiac Death.

Project description:In addition to its central role in mediating oxidation reduction in fuel metabolism and bioenergetics, nicotinamide adenine dinucleotide (NAD+) has emerged as a vital co-substrate for a number of proteins involved in diverse cellular processes, including sirtuins, poly(ADP-ribose) polymerases and cyclic ADP-ribose synthetases. The connection with aging and age-associated diseases has led to a new wave of research in the cardiovascular field. Here, we review the basics of NAD+ homeostasis, the molecular physiology and new advances in ischemic-reperfusion injury, heart failure, and arrhythmias, all of which are associated with increased risks for sudden cardiac death. Finally, we summarize the progress of NAD+-boosting therapy in human cardiovascular diseases and the challenges for future studies.

| S-EPMC7438569 | biostudies-literature

Mono(ADP-ribosyl)ation Enzymes and NAD<sup>+</sup> Metabolism: A Focus on Diseases and Therapeutic Perspectives.

Project description:Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ consuming enzymes. The synthesis and degradation of NAD+, as well as the transport of its key intermediates among cell compartments, play a vital role in the maintenance of optimal NAD+ levels, which are essential for the regulation of NAD+-utilizing enzymes. In this review, we provide an overview of the current knowledge of NAD+ metabolism, highlighting the functional liaison with mono(ADP-ribosyl)ating enzymes, such as the well-known ARTD10 (also named PARP10), SIRT6, and SIRT7. To this aim, we discuss the link of these enzymes with NAD+ metabolism and chronic diseases, such as cancer, degenerative disorders and aging.

| S-EPMC7827148 | biostudies-literature

Microbial NAD metabolism: lessons from comparative genomics.

Project description:NAD is a coenzyme for redox reactions and a substrate of NAD-consuming enzymes, including ADP-ribose transferases, Sir2-related protein lysine deacetylases, and bacterial DNA ligases. Microorganisms that synthesize NAD from as few as one to as many as five of the six identified biosynthetic precursors have been identified. De novo NAD synthesis from aspartate or tryptophan is neither universal nor strictly aerobic. Salvage NAD synthesis from nicotinamide, nicotinic acid, nicotinamide riboside, and nicotinic acid riboside occurs via modules of different genes. Nicotinamide salvage genes nadV and pncA, found in distinct bacteria, appear to have spread throughout the tree of life via horizontal gene transfer. Biochemical, genetic, and genomic analyses have advanced to the point at which the precursors and pathways utilized by a microorganism can be predicted. Challenges remain in dissecting regulation of pathways.

| S-EPMC2738131 | biostudies-literature

NAD+ metabolism governs proinflammatory senescence secretome

Project description:Cellular senescence is a stable cell growth arrest that is implicated in tissue aging and cancer. Senescent cells are characterized by an upregulation of proinflammatory and immunosuppressive cytokines and chemokines, which is termed as senescence-associated secretory phenotype (SASP). NAD+ metabolism plays a critical role in both tissue aging and cancer. However, the role of NAD+ metabolism in regulating the SASP is not well understood. Here we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the strengths of proinflammatory SASP during senescence. In contrast to downregulation of NAMPT during replicative senescence, NAMPT is upregulated during oncogene-induced senescence. NAMPT selectively regulates proinflammatory, but not immunosuppressive, SASP. NAMPT is regulated by HMGA1 through a distal enhancer element during senescence. HMGA1/NAMPT/NAD+ signaling axis promotes proinflammatory SASP through enhancing glycolysis and mitochondria respiration. Mechanistically, HMGA1/NAMPT promotes proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses p53-mediated inhibition of p38MAPK to enhance NFb activity. SASP regulation by NAD+ metabolism is independent of senescence-associated cell growth arrest. An increase in NAD+ levels is sufficient to convert SASP from low to high levels during replicative senescence. Together, we conclude that NAD+ metabolism governs the strengths of proinflammatory SASP. Given the tumor promoting effects of proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.

2019-03-14 | GSE111841 | GEO

NAD+ metabolism and cardiometabolic health: the human evidence.

Project description: Not available

| S-EPMC8318105 | biostudies-literature

NAD<sup>+</sup> metabolism: pathophysiologic mechanisms and therapeutic potential.

Project description:Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

| S-EPMC7539288 | biostudies-literature