Nicotinamide adénine dinucléotide

Résumé

Le nicotinamide adénine dinucléotide (NAD) est une coenzyme présente dans toutes les cellules vivantes. Il s'agit d'un dinucléotide, dans la mesure où la molécule est constituée d'un premier nucléotide, dont la base nucléique est l'adénine, uni à un second nucléotide, dont la base est le nicotinamide. Le NAD existe sous une forme oxydée, notée NAD+, et une forme réduite, notée NADH. Le NAD intervient dans le métabolisme comme transporteur d'électrons dans les réactions d'oxydoréduction, le NAD+ comme oxydant et le NADH comme réducteur. Le NAD intervient également dans quelques autres processus cellulaires, notamment certaines modifications post-traductionnelles — ADP-ribosylation — des protéines nouvellement synthétisées. En raison de l'importance de ces fonctions cellulaires, les enzymes impliquées dans le métabolisme du NAD font l'objet de diverses recherches pharmaceutiques. Le NAD peut être synthétisé in vivo à partir du tryptophane et de l'aspartate, deux acides aminés protéino

Source officielle

https://fr.wikipedia.org/wiki/Nicotinamide_ad%C3%A9nine_dinucl%C3%A9otide

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Pancreatic beta cells play a major role in the regulation of glucose homeostasis by secreting insulin in response to elevated blood glucose levels. A gradual deterioration of functional beta cell mass and the chronic elevation of blood glucose levels are central to development of type 2 diabetes. While the etiologies of Type 2 diabetes and age-related metabolic complications are complex, they are often associated with a decline of intracellular nicotinamide adenine dinucleotide (NAD+). NAD+ levels are maintained through the balance between its synthesis from NAD+ precursors and its degradation by several families of enzymes, including the sirtuin family of protein deacetylases, the ADP-ribosyl transferase enzymes (ARTDs or PARPs) and cADP ribose hydrolases (CD38). NAD+ declines are mostly associated with increased NAD+ consumption, which can be counteracted by dietary supplementation of NAD+ precursors. However, our knowledge on how different tissues utilize and respond to different NAD+ precursors for NAD+ synthesis is still incomplete. This, in turn, limits our ability to provide therapeutic benefits in clinical settings. In this project, we aim to understand the relevance of a particular NAD+ precursor, nicotinamide riboside (NR), in beta cell physiology and its potential use to treat beta cell dysfunction. To do so, we have used mice that are deficient for nicotinamide riboside kinase 1 (NRK1), the first and rate-limiting enzyme for the transformation of NR into NAD+. We demonstrate that NRK1 whole body knockout mice exhibit impaired insulin secretion after a meal or upon glucose challenge when fed a high fat diet. However, NRK1 deficiency in beta cell was not the causality for beta cell failure as differences observed in the NRK1 whole body KO mice were not phenocopied in NRK1 beta cell specific KO mice. Aged NRK1 whole body KO mice also exhibited dysfunctional beta cells and significant loss of insulin content and beta cell mass. Furthermore, NRK1 deficiency exacerbates the decline of NAD+ bioavailability and mitochondria function with age, even promoting fibrosis in multiple tissues. Together, our data suggests that endogenous NR metabolism is critical in maintaining whole body NAD+ homeostasis and to protect against mitochondria dysfunction and stress-related cell responses in pancreatic beta cells.

EPFL2022

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The progressive decline of muscle mass and function called sarcopenia is a multi-factorial process associated to frailty, disability, and low quality of life in the elderly. The co-factor nicotinamide adenine dinucleotide (NAD+) becomes a limiting factor in the course of aging and other pathological conditions. It has emerged as a major regulator of cellular metabolism, which is modulated by dietary precursors of the vitamin B3 family. So far, no direct link between sarcopenia and alterations in NAD+ metabolism has been reported. In this thesis, I have taken a multi-disciplinary approach combining molecular profiling in humans and dietary and genetic manipulations in rodents to characterize the skeletal muscle NAD+ metabolism in the context of muscle plasticity and aging. We have performed a multi-center study to characterize the molecular signature of human sarcopenia compared to age-matched controls. Sarcopenic participants of three cohorts in Singapore, the United Kingdom and Jamaica presented a prominent transcriptional signature of mitochondrial dysfunction, which translated into functional bioenergetic deficiency with lower mitochondrial protein expression and activity. Furthermore, we established a concurrent decrease in NAD+ content of sarcopenic muscle, which correlated to lower muscle strength and function in these patients. Supplementation with the dietary NAD+ precursor nicotinamide riboside (NR) was shown to improve pathological muscle conditions and revert age-related mitochondrial dysfunction and stem cell senescence in mice. To test whether boosting NAD+ through NR can be beneficial in the context of sarcopenia, we investigated the acute response to NR supplementation in young adult and old sarcopenic rats. Acute NR treatment efficiently increased NAD+ levels and normalized specific age-related gene expression signatures in old rats, in particular related to fibrosis. Interestingly, our transcriptional profiling also revealed that the molecular response to NR is partially blunted in aging and suggests that aged muscle could be in a state of partial NAD+ resistance. To investigate the role of endogenous NR as NAD+ precursor in the muscle, we studied mice deficient for NR kinases 1 and 2 (NRK1/2 dKO), the rate-limiting enzymes for NR salvage. NRK1/2 dKO mice develop normally, but exhibit elevated salvage of the NAD+ precursor nicotinamide (NAM) to maintain tissue NAD+. Thus, our results demonstrate for the first time that an endogenous NRK-dependent flux actively converts NR into NAD+ in healthy skeletal muscle. Moreover, we demonstrated that NRKs are required for muscle regeneration, as dKO mice failed to efficiently regenerate the NAD+ pool during the active phases of myofiber remodeling, which coincided with a transient delay of myofiber maturation. Conversely, dietary NR improved the activation of muscle stem cells and accelerated recovery of NAD+ levels in regenerating myofibers of wild-type mice. Altogether, this work demonstrates that both in humans and preclinical models, sarcopenia is tightly linked to mitochondrial bioenergetics and NAD+ metabolism. Dietary manipulation of NAD+ levels is a promising therapeutic strategy for the management of age-related muscle dysfunction for which we uncovered important mechanistic insights linking metabolic fluxes through the NAD+ pathway to physiological adaptations.

EPFL2019

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Nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) are crucial redox cofactors regulating energy metabolism, reductive biosynthesis and the antioxidant defense system. Besides their role as redox cofactors, NAD(P)s have more recently also been described as important signaling molecules, acting for example as cosubstrate of different enzymes such as the sirtuins and poly(ADP-ribose) polymerases (PARPs), involved in the control of important cellular functions. Highlighting their important role, an imbalance of their intracellular concentration has been associated with aging and different pathologies. Therefore, the development of methods enabling the accurate subcellular quantification of NAD(P) in live cells is of great importance. This thesis describes the development and application of two FRET-based semisynthetic biosensors for NADPH/NADP+ and NAD+ in live cells. These sensors, named NAD(P)-Snifits, possess a high dynamic range, high specificity, are pH insensitive and can be excited at long wavelenghts. By using ratiometric imaging and fluorescence lifetime imaging, we quantified free NADPH/NADP+ and NAD+ in different subcellular compartments in live cells. We report here, for the first time, that free NADPH/NADP+ is significantly higher in the mitochondria than in the cytosol and observed moderately higher NAD+ level in the mitochondrial matrix consistent with previous report. We have also demonstrated that NADP-Snifit can be used to monitor the dynamics of NADPH/NADP+ caused by oxidative stress using conventional widefield fluorescence microscopy. The easy handing and use of these sensors make it possible to study not only the kinetics of cellular H2O2 scavenging and NADPH regeneration rate, but also to monitor drug-related side effects. Finally, we measured the effect of different conditions and drug treatment mimicking calorie restriction on free cytosolic and mitochondrial NADPH/NADP+ and NAD+ by flow cytometry. We observed that all these treatments increased free cytosolic and mitochondrial NAD+ concentrations with various levels of efficiency, but had divergent effects on the different subcellular NADPH/NADP+. NAD(P)-Snifits have the potential of becoming valuable tools to study the NAD(P) metabolism in physiological relevant conditions. Their wide applicability, in particular with high-throughput methods such as flow cytometry opens the possibilities for their use in metabolic and drug screening of large libraries.

EPFL2018

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EPFL2018

EPFL2019

EPFL2022